SI9300094A - Heterocyclic compounds - Google Patents

Abstract

There are disclosed compounds of the general formula <CHEM> The heteroatom X is preferably oxygen, but may have other values. The group W is preferably a carbonyl group, but may have other values. The preferred heterocyclic ring is thus a 4-oxo-4H-1-benzopyran ring. This may have a wide range of R2, R3, R6 and R7 substituents. Y is a linking group, chosen from a wide range, but including -COO- , -CONH- , -O- , -SO2- and -SO2NH-. Z is an alkylene chain, and B is a complex amine. These compounds and their prodrugs, enantiomers, diastereoisomers, N-oxides and pharmaceutically acceptable salts are useful for the treatment of hypertension and urinary tract troubles associated with benign prostatic hypertrophy, and for the treatment of other diseases.

Description

Heteroatom X is preferably oxygen, but may have other meanings. The W group is preferably a carbonyl group but may have other meanings. The preferred heterocyclic ring is thus a 4-oxo-4H-1-benzopyran ring. This may have different substituents R2, R3, R6 and R7. Y is a linking group selected from a wide variety, but includes -COO-, -CONH-, -SO, 2- and -SO2- and -SO2NH-. Z is an alkylene chain and B is a complex amine. These compounds and their prodrugs, enantiomers, diastereoisomers, N-oxides and pharmaceutically acceptable salts are useful for the treatment of urinary tract hypertension and disorders associated with benign prostatic hypertrophy and for the treatment of other diseases.

-f.

RECORDS S.A., Chemical and Pharmaceutical Company

Heterobicyclic compounds

Description

The invention relates to heterobicyclic compounds and to pharmaceutical compositions containing them.

Flavoxate, which is 8- (2-piperidinoethoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran and has the formula

used as a pharmaceutical for urinary tract disorders and it has a smooth muscle relaxation effect that can be attributed to its calcium antagonist effect. This effect acts on the smooth muscle of the bladder, or may be related to the urinary center of the central nervous system.

The compounds of the invention described below include substantially more parts of the complex amines instead of the piperidine group. Further changes include alternatives to the ethoxycarbonyl group separating the amino moiety from the benzopyran ring, alternative 2-, 3-, 6- and 7-substitution patterns in the benzopyran ring, replacing the ring heteroatom with a sulfur atom or with a sulfinyl, sulfonyl or imine group, and / or 2,3-Dihydrogenation of the benzopyran ring. These structural variations give new compounds the ability to interact with different biological systems, as supported by the affinity of novel compounds for α _x -adrenergic and 5HT _1A -serotonergic receptors. Flavoxalate has virtually no affinity for these receptors.

Compounds of the invention

Compounds in the sense of ism have the general formula I .R.

wherein - represents a single or double bond;

X represents an oxygen or sulfur atom or an imino, alkylimino, sulfinyl or sulfonyl group;

W represents a valence bond or a carbonyl, thiocarbonyl, methylene or hydroxymethylene group;

R2 represents a hydrogen atom or an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl or aroyl group; wherein the substituents for the aforementioned substituted groups are one or more halogen atoms and / or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, diaUdlamino, acylamino, alkylsulfonylamino or benzoyl groups;

R ₃ represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy or aralkoxy group;

R ₆ represents a hydrogen or halogen atom or a nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino, cyano, hydroxy, alkoxy or alkyl group;

R _? represents a hydrogen atom or an alkoxy group;

Y means one of the following groups, each of which is obtained by having its left end end attached to the heterobicyclic ring and its right end end attached to the group Z

(Yl) -CO-, (Y2) -COO-, (Y3) -CONH-, (Y4) -CON (CH ₃ ) -, (Y5) -CON (OH) -, (Y6) -CH (OH) -, (Y7) -CH (Oalkyl) -, (Y8) -CH = CH-, (Y9) -CH = CH-COO-, (Υ10) -CH = CH-CONH-, (Υ11) -CH = NO-, (Υ12) -ch ₂ -, (Υ13) -ch ₂ coo-, (Υ14) -ch ₂ conh- (Υ15) -CH ₂ NH-, (Υ16) -CHjNCCH ^ -, (Υ17) -CH ₂ N (COCH ₃ ) -, (Υ18) -CH ₂ N (CONH ₂ ) -, (Υ19) -ch ₂ nhco- (Υ20) -CH ^ CH ^ CO-, (Υ21) -ch ₂ nh-conh-, (Υ22) -ch ₂ nhso ₂ -, (Υ23) -CRjO-, (Υ24) -CHjS-, (Υ25) -CH ₂ SO-, (Υ26) -ci ^ are, -, (Υ27) -CH ^ NH-, (Υ28) -CH ₂ SO ₂ N (CH ₃ ) -, (Υ29) -NH-, (Υ30) -N (CH ₃ ) -, (Υ31) -N (COCH ₃ ) -, (Υ32) -NCCONH ^ -, (Υ33) -NHCO-,

(Υ34) -N (CH ₃ ) CO-, (Υ35) -NH-CONH- (Υ36) -nhso ₂ -, (Υ37) -0-, (Υ38) -S-, (Υ39) -S0-, (Υ40) -S0 ₂ -, (Υ41) -so ₂ nh-, (Υ42) -SO ₂ N (CH ₃ ) -, (Υ43) -CONHO-, (Υ44) -CON (COCH ₃ ) -, (Υ45) -CSNH-, (Υ46) -CSN (CH ₃ ) -, (Υ47) -CON (O-p

(Υ48) -NHCOO- in (Υ49) -COS-;

Z represents a straight or branched alkylene group of 1 to 6 carbon atoms having optionally one hydroxy substituent; and

B stands for one of the following groups:

(WOULD)

in which Q represents a methylene or ethylene group and A represents one of the following groups:

(Al) a phenyl group substituted by one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups, (A2) 2-pyrimidinyl group and (A3) a group of the general formula

Ο

where it is defined as above and E represents an oxygen atom or a valence bond, (B2)

wherein each of L _x and L ₂ independently represents a hydrogen atom, a phenyl, 4-fluorobenzoyl or 2-oxo-1-benzimidazolyl group or a group of the general formula (CH ₂ ) _n -OA, where n is 0, 1 or 2, and A is defined as above, provided that L and L ₂ do not represent both hydrogen atoms, (B3)

in which each of R ₁₀ and R _{n is} independently a hydrogen atom or an alkoxy or alkylthio group, R ₁₂ represents a hydrogen atom or an alkyl group and n is 2 or 3,

wherein R ₁₂ is as defined above and R ₁₃ is a hydrogen atom or an alkoxy group, and (B5)

in which R _{12 is} defined as above.

If it is a double bond, W is a carbonyl group and X is an imino group, the ring may be tautomerized to form a 4-hydroxy-quinoline structure; such tautomeric compounds are included in the invention.

The invention also includes prodrugs, enantiomers, diastereoisomers, N-oxides, and pharmaceutically acceptable salts of compounds of general formula I.

The term prodrug is used herein to mean a derivative of a compound of general formula I in which the reactive groups, such as amino, imino or hydroxy groups (in particular as parts of W, R ₂ , R ₃ , R ₆ , Z, BI and B2, or in them) or acidic imino groups (e.g., those present in Y3, ΥΙΟ, Υ19, Υ27, Υ36 and Υ41) masked; a derivative that releases the compound only in the living body and thus has the same pharmacological effect on the body as the compound itself. The prodrugs can be prepared by altering the pharmacokinetic properties of the compound, e.g. by preparing the form of a compound by retarding or counteracting release, or otherwise modifying the metabolism, adsorption, distribution, and plasma half-life of the compound.

The compounds prepared in Examples 114 and 120 to 122 below are examples of prodrugs.

The group

we shall hereafter abbreviate as Fl. The preferred meanings of the substituents in the Fl group are as follows:

-—: double bond,

X: oxygen atom,

W: carbonyl group,

R ₂ : phenyl group,

R ₃ : methyl group,

R ₆ : hydrogen atom and

R _? : hydrogen atom.

The group having all these preferred substituents is the 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-yl group.

The preferred groups Z may represent are trimethylene and tetramethylene. Y preferably represents one of the groups Y2, Y3, Υ37, Υ40, Υ41 or Υ42. B preferably represents one of the groups BI or B3, in particular the 1- (2-methoxyphenyl) -piperazinyl group.

Other conventional abbreviations used herein include Me for methyl, Et for ethyl, Ac for acetyl, Alk for alkyl, THF for tetrahydrofuran, DMF for dimethylformamide, and DMSO for dimethylsulfoxide.

The effect of the adrenergic antagonist of the compounds of the invention makes them useful as agents that act on body tissues that are particularly rich in? -Adrenergic receptors (such as blood vessels, prostate and urethra). Therefore, the antiadrenergic compounds of the invention, which, on the basis of their receptor binding profile, have been found to be useful therapeutic agents for the treatment of e.g. hypertension and urinary disorders associated with, but not limited to, obstructive disorders of the lower urinary tract, including those caused by benign prostatic hypertrophy.

The serotonergic effect of the compounds of the invention makes them useful as tissue-acting agents, especially in the central nervous system where 5HT _1A receptors function. The 5HT _1A receptors are thought to regulate serotonin activity and release as well as the release of other nerve mediators and are found both presynaptic and postsynaptic. The compounds of the invention have a biological effect because they block binding between these receptors and their various specific ligands (e.g. serotonin). Accordingly, the compounds of the invention that exhibit 5HT _JA receptor interaction (found as such based on their receptor binding profile) may be useful therapeutic agents for the treatment of anxiety disorders and depression.

Surprisingly, the compounds of the invention (especially those showing affinity for both o-adrenergic and 5HT _1A- serotonergic receptors) exhibit high selectivity for the mammalian lower urinary tract, i.e., they are significantly more effective in antagonizing urethral contractions than in reducing blood pressure. In contrast, known α ₁ antagonists, such as prazosin, which is l- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine (GB 1156973), do not exhibit such selectivity (and in fact cause hypotension as the most common side effect), whereas flavone derivatives structurally similar to flavoxate such as terflavoxate, which is

8- (1,1-dimethyl-2-piperidino-ethoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride (EP 0072620) have no effect on urethral contractions. Of course, those compounds of the invention that are not selective for the lower urinary tract are preferred as antihypertensive agents, but even selective compounds can often be used as antihypertensives because of their low toxicity.

The compounds of the invention have also shown a good antagonist effect against potassium chloride-induced rat bladder contractions. This effect can be attributed to an antagonistic effect on calcium and make new compounds useful as spasms of the lower urinary tract (i.e., useful in the treatment of urinary incontinence, water-tightness syndrome and other similar disorders).

Most of the compounds of the invention exhibit low toxicity. Therefore, they can be used in large quantities, an advantage that often more than compensates for the relatively low level of performance of some of these compounds. Of course, compounds that exhibit both high potency and low toxicity are of course preferred.

The invention further provides a pharmaceutical composition comprising a compound of the invention or prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt of such compound to which a pharmaceutically acceptable diluent or carrier is admixed.

Synthesis of the compounds of the invention

The compounds of the invention can generally be prepared (unless the R ₆ groups and the substituents on R _{2 are} OH, NH ₂ or aminoalkyl and Υ = Υ15 or Υ29) as follows:

Path a:

By condensing the compounds Fl-Y-Z-L> where L is a halogen atom or leaving group, such as a tosyloxy group, with compound H-B. Condensation is preferably carried out, but not necessarily, at a temperature in the range of 20 to 140 ° C, in a polar solvent such as dimethylformamide or methanol, usually in the presence of a base such as potassium carbonate. Such condensations are shown below in Examples 1 to 3, 7 to 9,11,13 to 16, 21, 23 to 31, 38 to 42, 46 to 49, 54 to 59, 69, 73, 77, 78 and 84. See also Gibson's chapter in Patai, The Chemistry of the Amino Group, p. 45 et seq., Wiley Interscience, New York, 1968.

An alternative method of preparing the compounds of the invention is the condensation (under the same conditions as described in the previous paragraph) of the Fl-Y-H compound with the compound L-Z-B, wherein L is as defined above. This condensation is shown below in Examples 5, 6,66,79 and 81. Compounds where Y = Y15 or Υ29 can also be prepared along this path (see Gibson's chapter in Patai, supra).

Compounds of formula (I) bearing the NH ₂ group in R ₆ or as a substituent in R ₂ can be prepared by reduction of the corresponding compounds (I) wherein R ₆ or a substituent in R _{2 is} a NO ₂ group. Such reduction can be carried out with a Ni-Raney catalyst in a protic solvent selected from methanol, ethanol, isopropanol, water and mixtures thereof; or SnCl ₂ , H ₂ O, optionally in the presence of hydrochloric acid, either in a protic solvent such as methanol, ethanol, isopropanol, water, acetic acid or mixtures thereof, or in an aprotic solvent such as ethyl acetate; or with Fe and aqueous hydrochloric acid in a protic solvent such as methanol, ethanol, isopropanol, water and mixtures thereof.

The temperatures of the above reactions will be selected in the range of 20 to 100 ° C (J. March, Advanced Organic Chemistry, III Ed., Page 1103, Wiley Interscience, 1985). Examples of this reduction are given in Examples 94 and 124.

Compounds of formula (I) having the group NHAlk as a substituent in R ₆ can be prepared by monoalkylation from the corresponding parent compounds (I), where R ₆ = NH _2> This can be done e.g. by first reacting the amino compound (I) with excess trifluoroacetic acid anhydride, then reacting the resulting trifluoroacetyl derivative with an alkyl-L reagent, and finally removing the protection from the trifluoroacetyl alkyl derivative thus obtained by treatment with potassium carbonate in methanol or sodium ananimimine or sodium ananimimine dimethylsulfoxide. These metabolites are described in Examples 32 and 33 where they were performed on Y groups.

Alternatively, compounds of formula (I) having the groups NHAlk or N (Alk) ₂ can be obtained as a substituent of R ₆ or as a substituent in the phenyl group in R ₂ , by alkylation of the corresponding parent compounds (I), where R ₆ = NH ₂ , with suitable alkanals in the presence of a reducing agent such as sodium cyanoborohydride. Descriptions of these metabolites are given below in Examples 96 and 97.

Compounds bearing the OH group as R ₆ or as a substituent in R 1 can be prepared from the corresponding parent compounds (I) which are substituted in these positions by alkoxy. This can be achieved by treating the parent compounds e.g. with BBr ₃ in dichloromethane at 0-40 ° C (TW Greene, Protective Groups and Organic Synthesis, page 87, Wiley Interscience, 1981) or according to other methods described in the same reference.

Compounds of general formula I in which - represents a single bond can be obtained either by selectively hydrogenating the corresponding compounds in which - represents a double bond or by converting suitable starting materials in which the bond 2,3 is already saturated, wherein such starting materials are obtained according to reaction schemes 4, 6 to 9, 11, 12 and 14 below. This second route is shown in Example 87 below, and is particularly preferred if it contains the nitro group in question because hydrogenation could convert the nitro group to an amino group. Selective hydrogenation can be carried out using either hydrogen in the presence of a metal or metal oxide catalyst (e.g. palladium on carbon or platinum dioxide) in a protic solvent at 20 to 120 ° C (EH Rodd, Chemistry of Carbon Compounds, Vol. IVB, page 903 , Elsevier, 1959); or di (isobutyl) aluminum hydride in an aprotic solvent (e.g. tetrahydrofuran and / or dichloromethane) at -70 to 0 ° C (H. Sarges et al., J. Med. Chem., 33, 1859,1990).

Compounds in which W represents a hydroxymethylene group and the bond 2,3 is saturated can be obtained by reduction of the corresponding compounds in which W represents a carbonyl group and the bond 2,3 is saturated with sodium borohydride as indicated below in Example 123.

In some cases, the compound of general formula I can be prepared by converting other (parent) compounds of the invention. Such conversions include:

Potb: Fl-CO-Z-B F1-CH (OH) -Z-B with reduction as shown below in Examples 17 to 20.

Route c: F1-CH (OH) -Z-B-> Fl-CH (Oalkyl) -Z-B by etching as shown below in Example 22.

Route d: Fl- (CH ₂ ) _n -NH-ZB ^ Fl (CH ₂ ) _n -N (CH ₃ ) -ZB where n = 0 or 1, by N-methylation, as shown below in Example 35.

Route e: Fl- (CH ₂ ) _n -NH-ZB ^ Fl- (CH ₂ ) _n -N (COCH ₃ ) -ZB where n = 0 or 1, by N-acetylation as shown below in Example 36 .

Potf: Fl-CCH ^ -NH-Z-B-► Fl-iCH ^ -h ^ CONH ^ -Z-B where n = 0 or 1, by metabolism with potassium isocyanate, as shown below in Example 50.

Route g: F1-CH (OH) -Z-B -> Fl-CO-Z-B by oxidation as shown below in Example 51.

Route h: Fl-Y-Z-B-> Fl-Y-Z-B (N-oxide) with oxidation as shown below in Examples 43 and 122.

Pathways: H ₂ N-F1-YZB ^ CH ₃ CONH-F1-YZB (where HjN-Fl denotes a Fl group in which R _{6 is an} amino group or includes a R ₂ amino group) using the N-acylation method described below in cases 36 and 95.

Path i: F1 (R ₆ = ΝΗ ^ -Υ-Ζ-Β - F1 (R ₆ = CH ₃ SO ₂ NH) -YZB by amidification using the method described below in Example 112.

Path to:

or

7l-YZN ~ -C5 ₂

zN (Aik) -cs ₂ - r ° Tf or Fi-Υ-Ζ-Nn-C

->? l-Y-Z-N (Alk) -Cai

by N-alkylation using the procedure described below in Examples 35 and 62.

Some compounds can be prepared by addition reactions. E.g. those in which Z contains a hydroxy substituent can be prepared by addition via an epoxy group.

Paths: Fl-V-CI ^ -CH-OR ^ + HB-> F1-Y-CH ₂ -CH (OH) -CH ₂ -B as shown below in Example 45.

Addition via double bond is also possible, e.g.

Path m: Fl-V-CH-O ^ + HB - F1-Y-CH ₂ -CH ₂ -B as shown below in Examples 37,63 and 82.

Other synthesis schemes include the formation of Y, Z or B during the reaction, e.g.

Path n: F1 - (X) - (Q) -C1 + A-HN-ZB F1- (X) - (Q) -N (A) -ZB (where X = bond, CH ₂ or CH = CH , Q = CO or SO ₂ and A = H, alkyl or OP _r , wherein P _{r is a} protecting group) as shown in Example 12 (particularly preferred) and in cases 60,61,64,67,68,72,87 , 88.93,

98,116,129 and 130, respectively.

The same compounds may also be prepared by other routes, including F1- (X) -COOH + A-NH-ZB in the presence of a coupling agent (e.g. dicyclohexylcarbodiimide, Ν, Ν'-carbonyldiimidazole or diethyl cyanophosphonate), optionally in the presence of a promoter ( e.g., 4-dimethylaminopyridine or Nhydroxybenzotriazole) in an aprotic or chlorinated solvent (e.g. dimethylforma 13 medium, chloroform) at -10/140 ° C (Albertson, Org. React., 12, 205-218, 1962; Doherty et al., J Med. Chem., 35, 9,1992; Staab et al., Newer Methods Prep. Organic Chem., 5,61,1968; Ishihara, Chem. Pharm. Buli., 39, 3236,1991); as shown in Examples 80, 86, 89, 90, 92, 99 to 111, 113 to 115, 117 to 119 and 128.

F1- (X) -COOH + A-NH-ZB without solvent at 150-220 ° C (Mitchell et al., J. Am. Chem. Soc. 53, 1879, 1931) or in high boiling point ether solvents (e.g. diglime);

Fl- (X) -COO-Alk + A-NH-ZB, optionally in the presence of a coupling agent (eg trimethylaluminum) in an aprotic and / or chlorinated solvent (eg hexane, dichloromethane) at -10/80 ° C, or solvent free at 80 to

180 ° C (S. M. Weinreb et al., Tetrahedron, 4171, 1977); M. F. Lipton et al., Org. Synth. 59,49,1979);

F1- (X) -COOH + aHryl chloroformate in the presence of a tertiary amine (e.g. triethylamine), followed by the addition of A-NH-Z-B at 0 to 80 ° C; where appropriate, a promoter (e.g., 1-hydroxypiperidine) may be added before the amine is added (Albertson, Org. React., 12,157,1962).

Path o: F1-COC1 + HS-Z-B Fl-Υ49-Ζ-Β

Path p: F1-COC1 + HO-Z-B -> Η-Υ2-Ζ-Β as shown below in Example 10.

Path q: F1CHO + HjNO-Z-B- * Fl-ΥΠ-Ζ-Β as shown below in Example 70.

Potr: Fl-CHO + A-HN-Z-BF1-CS-N (A) -ZB (where A = H or CH ₃ ) in the presence of sulfur in an aprotic solvent, e.g. DMF or pyridine, at 60-120 ° C (M. Carmack et al., Org. Reaction., 83, 1947; R. Benassi et al., Org. Magn. Res., 15, 25,1981), such as shown below in Example 83.

Path s: Fl-NHj + HCO-Z-B - Π-Υ29-Ζ-Β as shown below in Example 34.

Pott: F1-Y-CH ₃ + HO-CH ₂ -B - * F1-Y-CH ₂ -CH ₂ -B as shown below in Example 4.

Then: F1-CH = CH-CONH2 + HOCH ₂ -BF1-Y10-CH ₂ -B.

Path to:

Fl-YZN ₃ + HCO

K

Fl-YZB ₃ before reducing conditions as shown below in Example 44.

Pot w:

R. _c

F1-YZ-NH ₂ + L- (CH ₂ ) n-0 fi-yzb ₃

K ..

as shown below in Examples 74,75 and 76.

Fl-Υ-Ζ-ΝΗ + L-CH ₂

- Fl-YZB ₄

Fl-Υ-Ζ-Β as shown below in Example 52.

Potx:.

. F1-YZ-HN ₂ + VJM as shown below in Example 65.

Path in: F1-Y-Z-CHO + HB - »Fl-Υ-Ζ-Β as shown below in Example 53.

Path with: F1- (X = S) -YZB - F1 (X = SO or SO ₂ ) -YZB by oxidation with hydrogen peroxide in acetic acid or other oxidizing agents in the presence of acid.

One skilled in the art will recognize that all of the above synthetic routes b) to y) can be simplified provided that the reacting intermediate does not carry additional groups sensitive to the same reactants (e.g., CO, NHj, NHAlk or OH groups) . Compounds of formula I bearing such reactive groups can be prepared by routes b) to y) provided that the reactive groups present in the starting materials are pre-protected and then digested after removal, as shown in Example 71. Different examples of protection and deprotection for different reactive groups can be found in TW Green, Protective Groups in Organic Synthesis, Wiley

Interscience, 1981 (2nd Edition 1991).

Alternatively, non-reactive groups (e.g. NO ₂ ) can be left unconverted during the first metabolism and subsequently converted to reactive (e.g. NH ₂ ) as the final step of the pathway. See, e.g. path a).

Which synthesis techniques we give preference depends on the compound we want to synthesize, but path n) is generally preferred for the compounds that can be prepared thereafter. Additional synthesis methods will be apparent to those skilled in the art.

Output materials

The starting materials (Fl-YZL and Fl-YH and others) used in the preparations described above can be prepared according to their fabric from simple compounds such as F1-C00H, F1-CH0, F1-COC1, F1-NH ₂ and F1 -0H with conversions known to the person skilled in the art. Many such conversions are described in detail below. Many of these simple compounds (Fl-COOH, F1-CH0, F1-COC1, F1-NH ₂ and F1-0H) are commercially available or have been reported in the literature. Unavailable ones can be synthesized according to one or more of the following reaction Schemes 1 to 16.

Reaction Scheme 1 leads to compounds in which W is a carbonyl group and X is an oxygen atom.

SCHEME 1

A = co ₂ ch ₃ , co ₂ c ₂ h ₅ , no ₂ , ch = chch ₃ , B = CO ₂ H, NH ₂

The rate of la

Procedure without intermediate phenyl ester isolation:

R ₃ CH ₂ COC1 or (R ₃ CH ₂ CO) ₂ O and Lewis acid (eg A1C1 ₃ or

ZnCl ₂ ), without solvent or in an aprotic solvent (eg nitrobenzene or chlorinated solvent) at 20 to 180 ° C.

Procedure for the isolation of an intermediate phenyl ester:

RgCI ^ COCl or (R ₃ CH ₂ CO) ₂ O is heated with starting material or other esterification methods such as the Schotten-Bauman method. The isolated ester is then heated in nitrobenzene or other non-protic solvent (eg chlorinated solvent) or without solvent at all at 20 to 180 ° C in the presence of Lewis acid, such as A1C1 ₃ or ZnCl ₂ (AM Blatt, Org. React., 1,342,1942) .

Rate lb

R ₂ COC1 or (R ₂ CO) ₂ O and R ₂ COONa alone or in a non-protic solvent with high boiling point (such as o-dichlorobenzene) at 150 to 220 ° C; this metabolism also permits the direct conversion of compounds (2) to compounds (6) if the compounds (2) have A = COOH;

R ₄ OAlkjj in the presence of HClO ₄ at 20-40 ° C or in pyridine in the presence of piperidine at 60 to 80 ° C;

I ^ COCl or (R ₂ CO) ₂ O in a chlorinated solvent at -10 to 120 ° C in the presence of a base such as 1,8-diazabicyclooundecene (DBU).

The rate of lc

RjCOCl in pyridine at 20 to 100 ° C or a non-protic solvent at 0 to 80 ° C, optionally in the presence of a base such as NEt ₃ or 4-dimethylaminopyridine.

The rate of ld

K ^ COg in acetone or methyl ethyl ketone at 20 to 80 ° C;

NaH in DMSO or THF at 0 to 40 ° C;

KOH or potassium t-butoxide in pyridine at 20 to 100 ° C.

The rate only

HCl or H ₂ SO ₄ in AcOH at reflux or in alcohol (MeOH, EtOH, isopropanol) at 20 ° C to reflux temperature;

CF ₃ COOH in dichloromethane at 20 to 40 ° C; p-toluenesulfonic acid in benzene or toluene at reflux.

The rate of lf

RjCOCl and K ^ COj or KOH in water and phase transfer catalyst in benzene or toluene at reflux;

R ₂ COOAlk and lithium bis (trimethylsilyl) amide or lithium diisopropylamide in THF at -78 ° C.

The rate of lg

If A is a COOCH ₃ group or a COOC ₂ H _{5 group} :

NaOH in aqueous EtOH and 0 to 75 ° C;

LiOH in aqueous DMF, MeOH or THF or mixtures thereof at 10 to 100 ° C;

HCl in an aprotic solvent such as dioxane at 60 to 120 ° C.

If A is a group NO ₂ :

Reduction with a Ni-Raney catalyst in a protic solvent (eg isopropanol) or a mixture of protic solvents at 20 to 100 ° C.

Reduction with hydrogen and catalyst (e.g. Raney nickel or Pd / C) in a protic solvent (e.g. MeOH, EtOH, isopropanol or mixtures thereof) at 20 to 100 ° C.

Reduction with SnCl ₂ in the presence of aqueous HCl in a protic solvent (eg AcOH) at 20 to 100 ° C.

Reduction in the presence of Fe and aqueous HCl in a protic solvent at 20 to 100 ° C. If A is a group CH = CHCH ₃ :

Oxidation with Na ₂ Cr ₂ O ₇ or other oxidizing agents such as KMnO ₄ in acetone / H2SO ₄ at 0 to 100 ° C.

Reaction scheme 2 leads to compounds in which X represents a sulfur atom or a sulfinyl or sulfonyl group and W represents a carbonyl group. O-mercaptobenzoates (1) are commercially available or can be prepared by known methods, e.g. by conversion of the corresponding o-alkoxycarbonyl-benzenediazonium salts after treatment with potassium ethylxanthate (M. S. Cohen et al., J. Org. Chem., 18,1394,1953).

SCHEME 2

Oh

O O

Level 2a

R ₂ COCH (R ₃ ) CN or R ₂ COCH (R ₃ ) COOAlk in polyphosphonic acid at 50 to 120 ° C.

R ₂ C = C-COOAlk and A1 ₂ O ₃ in an aprotic solvent (eg Et ₂ O) at 0 to 40 ° C. R ₂ C = C-COO Alk and base in an aprotic solvent (eg THF or DMF) at 20 to 140 ° C.

In both latter cases, treatment with polyphosphoric acid at 50 to 120 ° C is followed. Level 2b

NaOH in aqueous EtOH at 40 to 75 ° C.

LiOH in aqueous DMF at 40 to 100 ° C.

Level 2c

Stoichiometric 30% H ₂ O ₂ in AcOH at 25 to 60 ° C. m-chloroperbenzoic acid in chloroform at 0 to 30 ° C.

The rate of 2d% H ₂ O ₂ in AcOH at 50 to 80 ° C.

Reaction Scheme 3 leads to compounds in which R _? represents a methoxy group, W represents a carbonyl group and X represents an oxygen or sulfur atom. Compounds (1) can be prepared according to reaction schemes 1 and 2 from the corresponding phenols or thiophenols (unsubstituted in position 2 or 6 with COO Alk or NO ₂ ).

SCHEME 3

Oh

CK.

CJ

II

Level 3a

HCHO and gaseous HCl in AcOH containing aqueous HCl (d = 1.18) at 50 to 100 ° C (P. Da Re et al., Ann. Chim., 46,904,1956).

This method can be used if R _{3 is} different from H or CH ₂ OH.

The resulting intermediates 2 can be converted using known methods to starting materials suitable for the preparation of the desired compounds of the invention (see intermediate LXIX).

Simple 2,3-dihydro intermediates (—- = single bond) can be prepared according to reaction scheme 4 provided that other reactive groups, which may be present (e.g. NH ₂ , OH), have been previously protected as described before. The compounds (4) thus obtained can be converted by the method from step lg to the corresponding derivatives, where A = COOH or NH ₂ .

SCHEME 4

7

Level 4a

R ₂ -CHO, aqueous NaOH in EtOH or other protic solvent.

R - CHO, NaH or potassium t-butoxide in THF (or other dipolar aprotic solvent) at 0 to 150 ° C.

Level 4b

Mineral acid (eg HCl or H ₂ SO ₄ ) in water or other protic solvent (eg EtOH, AcOH) at 0 to 100 ° C.

Level 4c

R _{2 is} -CHO, O, IN to IN aqueous NaOH or another suitable base in a protic solvent.

R ₂ -CHO, pyrrolidine in a protic (e.g. MeOH) or polar aprotic solvent at 0 to 100 ° C (HJKabbe, Synthesis, 1978, p. 886).

Level 4d

Lithium diisopropylamide in THF at 0 to 20 ° C, then trimethylsilyl chloride and organic base (e.g. NEt ₃ ) (SE Kelly et al., J. Org. Chem., 56.1325,1991).

Level 4e

R ₂ -CHO in a chlorinated solvent (e.g. dichloromethane) at -78 ° C followed by TiCl ₄ or other Lewis acid (SE Kelly et al., J. Org. Chem., 56.1325,1991).

Level 4f

Lithium diisopropylamide in THF at -78 ° C, then R ₂ -CHO (A. Banerij et al., Tetrahedron Letter, 1979,3685).

Level 4g

R ₂ -CH = CR ₃ COC1, Lewis acid (eg A1C1 ₃ ) in a suitable solvent (eg nitrobenzene) or without solvent at 20 to 180 ° C.

Level 4h

R2-CH = CR ₃ COOAlk, triethylbenzylammonium hydroxide in an aprotic solvent (eg benzene) or solvent-free at 50 to 150 ° C, then aqueous NaOH in MeOH at 20 to 50 ° C or LiOH in aqueous DMF. (In this case, compounds having A = COOH ₃ or COOC ₂ H ₅ are also hydrolyzed to compounds having A = COOH).

Level 4i

Concentrated H ₂ SO ₄ or P ₂ O ₅ or polyphosphoic acid or Levvis acid in nitrobenzene or toluene or without solvent at 0 to 180 ° C. (In this case too, hydrolysis of A = COO Alk in A = COOH occurs).

Simple starting materials, where R ₃ = OH or OR _g , where R _{g is} alkyl or aralkyl, can be prepared according to reaction scheme 5, where A has the same meaning as in reaction scheme 1. Compounds (1) and (2) (which are the same as (2) and (4) in reaction scheme 4, but R ₃ = H) can be prepared according to reaction scheme 4 from the corresponding phenols or thiophenols, where R ₃ = H. Compounds (4) used in reaction scheme 5 can be prepared by known methods from the corresponding salicylates or thiosalicylates (see J.March, Advanced Organic Chemistry, 486, John Wiley and Sons, New York, 1985; L. Rene et al. ., Eur. J. Med. Chem. - Chim. Ter., 4, 385, 1977 and references cited therein). Substituent A in compounds (3) and (6) of reaction scheme 5 can be converted by the procedures from step lg to substituent B as defined in reaction scheme 1.

SCHEME 5

Level 5a

Aqueous NaOH in an alcoholic solvent (e.g. MeOH or EtOH) followed by 30% H ₂ O ₂ at -10 to -78 ° C (ND Meyer et al. J. Med. Chem. 34,736,1991 and there cited references). (Not if A is CH = CH-CH ₃ ; if A = COOR, it is converted to COOH at the same time).

Level 5b

If —- = single bond:

Amyl nitrite or other alkyl nitrite without solvent or in a suitable solvent (eg EtOH or benzene) in the presence of a catalyst, such as 37% HCl (Org. React., 7, 327, 1953 and references cited therein); then aqueous H 2 SO ₄ in a protic solvent (eg. AcOH) at 10 to 100 ° C (Acheson RM, An Introduction to the Chemistry of Heterocyclic Compounds, 347, John Wiley and Sons, New York, 1976).

If ie —- = double bond:

Lithium diisopropylamide in dry THF at -78 ° C followed by AcOH and 30% H ₂ O ₂ (BDM Cunningham et al., Anti-Cancer Drug Design, 7,365,1992).

Level 5c

R ₂ -CH = CH-NO ₂ (1 to 1.5 equivalents) in a suitable solvent (e.g. diisobutyl ether, DMSO or DMF) in the presence of a base (e.g. KOH or NaOH) in a catalytic or stoichiometric amount at 20 to 150 ° C (see L. Rene, supra, and T. Sakakibara et al., Buli. Chem. Soc. Jpn., 51.3095,1978).

Step 5d% H ₂ O ₂ , NaOH or other base (e.g. NEt ₃ ), in a protic solvent such as MeOH, at 20 to 100 ° C (SR Deshpande et al., Synthesis, 835, 1983) or photolysis, or alkaline hydrolysis (Rao TS et al., Heterocycles, 22,1377,1984), or KO ₂ in benzene containing 18-crown-6 ether, at 20 to 100 ° C (Rao TS, Heterocycles, 26,2117,1987 ). (Not if A is CH = CH-CH ₃ ; if A = COOR, it is converted to COOH at the same time).

Level 5e

R ₈ L, wherein L is a leaving group (eg. Alkylsulphate, halogen, tosyl) and a base (eg. C ^ CO ^ NaH, KOH, NaOH or LiOH) in a suitable solvent (eg. THF, DMSO, DMF, benzene) in the the presence or absence of a phase transfer catalyst (eg benzyltriethylammonium bromide) at 0 to 180 ° C.

Level 5f

According to the methods in step lb.

Reaction scheme 6, in which A has the same meaning as in reaction scheme 1, leads to compounds in which W represents a thiocarbonyl group. Compounds (1) and (2) from reaction scheme 6 can be prepared according to reaction schemes 1, 2, 4 and 5. Substituent A in compound (4) in reaction scheme 6 can be converted by the processes from step lg to substituent B as defined in reaction scheme 1.

SCHEME 6

O O

3

Level 6a

P ₂ S ₅ in pyridine at 50 to 100 ° C (Stavaux et al., Buli. Soc. Chim. Fr., 2082, 1967).

Level 6b

P ₂ S ₅ or B ₂ S ₃ or SiS ₂ or Lawesson's reagent in a chlorinated solvent (eg chloroform) or in an aromatic solvent (eg benzene, toluene, xylene) at reflux (Dean et al., J. Chem. Soc C, 2192,1963; RK Razdan et al., J. Med. Chem., 21,664,1978; K. Clausen et al., Tetrahedron, 37,3635,1991.

Level 6c

COC1 ₂ without solvent or with an inert solvent (e.g. benzene) at 40 to 90 ° C (A. Schonberg et al., Chem. Ber., 101,701,1968).

Level 6d

Thioacetic or thiobenzoic acid or potassium diethylxanthate in a suitable solvent (eg benzene) at reflux (A. Schonberg, supra).

Reaction Scheme 7, in which A has the same meaning in as Reaction Scheme 1, leads to compounds in which W represents a methylene or hydroxymethylene group. Compounds (1), (2) and (4) of reaction scheme 7 can be prepared according to reaction schemes 1, 2, 5 and 6. Substituent A in compounds (7) of reaction scheme 7 can be converted by the procedures from step lg to substituent B, as defined in reaction scheme 1.

Level 7a

1,2-ethanedithiol or 1,3-propanedithiol in an aprotic solvent (eg dichloromethane or benzene or toluene) at 0 to 110 ° C in the presence of a catalyst (eg p-toluenesulfonic acid or boron trifluoride etherate).

Level 7b

R ₂ COCH ₂ R ₃ in a suitable solvent mixture (eg EtOAc or dichloromethane plus EtOH or MeOH) saturated with gaseous HCl at 0 to 40 ° C, then aqueous HClO ₄ in AcOH at 20 to 100 ° C (L. Jurd , Tetrahedron, 28,493,1972).

Level 7c

LiAlH ₄ in THF at reflux (if A is different from COOR and NO ₂ ).

ZnJ ₂ and sodium cyanoborohydride (6 equivalents) in a chlorinated solvent (e.g.

1,2-dichloroethane) at room temperature to reflux (C. K. Lau et al., J. Org. Chem., 51, 3083,1986).

Level 7d

Raney nickel in an alcoholic solvent (e.g. isopropanol) at room temperature to reflux (Hilton et al., J. Am. Chem. Soc., 90,6887,1968).

Level 7e

NaBH ₄ in a suitable solvent (e.g. MeOH or EtOH or DMSO) at -10 to 50 ° C (L. Jurd, supra).

LiAlH ₄ in THF (or other suitable solvent) at 0 to 50 ° C (if A is different from COOR or NOJ (Degani et al., Ann. Chim., 61, 793,1971; Kurosawa, Buli. Chem. Soc. Soc. Jpn., 51,1175,1978).

Level 7f

Trityl perchlorate in acetonitrile at room temperature (Degani et al., Supra). Level 7g

Melting with P ₂ O ₅ at 80 to 180 ° C (Hortmann et al., J. Am. Chem. Soc., 96, 6118,1974).

Level 7h

NaBH ₄ in EtOH or other suitable solvent at 0 ° C until reflux (K. Hanaya, Buli. Chem. Soc. Jpn., 40,1884,1967).

Hydrogen (0.98 to 9.8 bar) in EtOH (or other suitable solvent) in the presence of a catalyst such as 5% or 10% Pd / C or Raney nickel or PtO ₂ at room temperature up to 80 ° C (K. Hanaya, supra). Not if A is CH = CHCH ₃ . If A = NO ₂ , it is simultaneously reduced to NH ₂ .

Aluminum triisopropoxide in isopropanol at room temperature up to 92 ° C.

Reaction scheme 8 shows the preparation of simple starting materials, such as (4), (5), (6) and (9), where A has the same meanings as in reaction scheme 1. Compounds (1), (2), (3), (7) and (8) can be prepared according to reaction scheme 1, 2, 4, 5, 7, 9 and 11. Substituent A in compounds (4), (5), (6) and (9) of reaction scheme 8 can be is converted by the procedures from step lg to substituent B as defined in reaction scheme 1.

SCHEME 8

R ₈ = H, Ac

Level 8a

Pb (OAc) ₄ in a suitable solvent (e.g., benzene, toluene) at reflux (GA Russel et al., J. Am. Chem. Soc., 1906,1975).

Level 8b

NaBH ₄ in alcohols (see reaction scheme 7, step 7a), then alkaline hydrolysis (if A = COOR, can be converted to COOH at the same time).

Aluminum isopropoxide as described in reaction scheme 7, step 7f. Diborane in THF at -10 ° C to room temperature, then aqueous H ₂ O ₂ in the presence of NaOH (not if A CH = CH-CH ₃ ; if A = COOR, converted to COOH at the same time). (Kirkiacharian et al., CR Hebd. Seances Acad. Sci. Ser. C, 289, 227, 1979).

LiAlH ₄ and A1C1 ₃ in a suitable solvent (e.g. THF) at 0 ° C to reflux (not for A = COOR or NOJ (Bokadia et al. J. Chem. Soc. 4663,1961).

Level 8c

Hydrogen (98 bar), copper chromite in EtOH at 140 ° C, see MA Vickars, Tetrahedron, 20, 2873, 1964. If A = NO ₂ , it is simultaneously converted to the NH ₂ group.

Level 8d

KMnO ₄ in t-butanol (or other suitable solvent) in the presence of aqueous NaOH at -10 to 0 ° C (K. Hanaya, Buli. Chem. Soc. Jpn., 40, 1884, 1967). (Not if A is CH = CH-CH ₃ ). (See also AH Haines, Methods for the Oxidation of Organic Compounds, Academic Press Inc, (London), 1985, Section 3.2.2).

Osmium tetroxide (see AH Haines, supra, section 3.2.1) in a suitable solvent (e.g., EtOJ at room temperature (Baranton et al., Buli. Soc. Chim. Fr., 4203,1968) (not if A is CH = CH-CH ₃ ).

Aqueous H ₂ O ₂ in formic or acetic acid at -20 to -50 ° C; then NaOH, H ₂ O, 45 ° C (Baranton et al., supra; AH Haines, supra, section 3.2.7). (Not if A is CH = CH-CH ₃ ; if A = COOR, it is converted to COOH at the same time). Silver acetate and iodine in moist AcOH at 0 to 20 ° C (K. Hanaya, supra; AH Haines, supra, chapters 3.2.3,3.2.4,3.2.9) (not if A CH = CH-CH ₃ ).

The rate of 8e% H ₂ O ₂ in the presence of NaHCO ₃ in benzonitrile at 0 to 110 ° C, followed by LiAlH ₄ in THF at 0 to 40 ° C (not for A = COOR and CH = CH-CH ₃ ) (Clark et al., Austr. Journ. of Chem., 27, 865, 1974).

Level 8f

Hydrogen (0.98 to 49 bar) in a suitable solvent (eg EtOH) in the presence of a metal catalyst (eg PdCl ₂ ) at room temperature up to 78 ° C. If A = NO ₂ it is converted to NH ₂ at the same time). (Bolger et al., Tetrahedron, 23, 341, 1967).

Level 8g

See Level 8b (Clark et al., Supra).

Grade 8h

0.4 M cerium trichloride heptahydrate in MeOH, in a suitable solvent (e.g. MeOH); then NaBH ₄ at 0 to 78 ° C (WO 89/06650).

NaBH ₄ in diglyms at 0 ° C to reflux (GP Thakar, Indian J. Chem., 3, 74, 1965) (if A = NO ₂ , converted to NH ₂ ).

NaBH ₄ and A1C1 ₃ in a suitable solvent (e.g. THF or benzene) at 0 ° C to reflux (not with A = COOR) (GP Thakar, above).

Diborane at THF at room temperature (not if A is CH = CH-CH ₃ ) (GP Thakar, above).

Simple starting materials having W = CH2 and a single bond in position 2,3 can be prepared according to reaction scheme 9, where A has the same meanings as in reaction scheme 1. Compounds (1) from reaction scheme 9 can be prepared according to reaction scheme 6 Compounds (1) of reaction scheme 9 may alternatively be obtained from compounds (2) by converting them to a 4-toluenesulfonic acid ester or a methanesulfonic acid ester or to a halogen derivative which can be converted by nucleophilic substitution with a thiol to a thioether derivative ( 1). These simple conversions can be performed by techniques known to those skilled in the art. Compounds (2) of reaction scheme 9 can be prepared according to reaction scheme 7. Compounds (3) of reaction scheme 9, wherein P = OC (S) -aryl or OC (S) -heteroaryl or OC (S) O-alkyl, or OC (S) O-aryl or OC (S) S-alkyl can be obtained by reacting the compounds (2) with a suitable chlorothioformate or chlorothiocarbonate or 1,1'thiocarbonyldiimidazole, as described in J. Org. Chem., 55, 924, 1990 and Synthesis, 362,1991 and references cited therein. Compounds (4) can be obtained from compounds (1) or (3) by simple elimination reactions with bases. Compounds (5) can be obtained according to reaction scheme 4. Substituent A in the compounds (6) of reaction scheme 9 can be converted by the processes from step lg to substituent B as defined in reaction scheme 1.

SCHEME 9

r ₈

P = alkyl, aryl, heteroaryl, H or zero = halogen, O-tosyl, O-mesyl, OC (S) aryl, OC (S) heteroaryl, 1-imidazolyl, OC (S) O-aryl, OC (S) O-heteroaryl

Level 9a

Raney nickel in a suitable solvent (eg isopropanol) at room temperature up to 100 ° C. If desired ₂ is converted to NH2 simultaneously

Triethyl tin hydride in benzene or other aromatic solvent at 30 to 150 ° C. For other methods similar to nickel chloride and NaBH ₄ in MeOH or boranpyridine complex in trifluoroacetic acid or dichloromethane in the presence of A1C1 ₃ , see J. March, Advanced Organic Chemistry, page 728, J. Wiley and Sons, New York, 1992 and cited therein. references. (Not if A is CH = CH-CH ₃ ).

Level 9b

Hydrogen with catalyst according to reaction scheme 8, step 8f. If A is NO ₂ , it is converted to NH ₂ at the same time.

Level 9c

If P is an O-C derivative:

Tributyltin hydride or tris (trimethylsilyl) silane in the presence of azaisobutyronitrile in a suitable solvent (e.g. toluene) at 80 to 150 ° C (M. Drescher, Synthesis, 362,1991; M. Sekine, J. Org. Chem., 55, 924 , 1990).

Silane (e.g. triethylsilane or diphenylsilane) in a suitable solvent (e.g. dichloromethane) at -20 ° C to reflux in the presence of CF ₃ COOH or BF ₃ (FM Mauser, J. Org. Chem., 55,555,1990).

Triethyl chlorosilane, sodium iodide in acetonitrile; then Zn powder in AcOH and acetonitrile at room temperature up to 80 ° C (T. Morita et al., Synthesis, 32, 1981).

If P is halogen or an O-S derivative:

A reducing agent (e.g., sodium cyanoborohydride in hexamethylphosphorylthriamide or NaBH ₄ in DMSO) selected from those listed in J. March, Advanc. Org. Chem., J. Wiley, New York, 1992, Chapter 0-76,0-77.

Level 9d

Hydrogen (0.98 to 4.9 bar) in a suitable solvent (e.g. EtOH) in the presence of a catalyst (e.g. 10% Pd / C at 50 to 78 ° C) (Sarcevic, Helv. Chim. Acta, 56, 1457, 1973). (IfA = NO ₂ is converted to NH ₂ at the same time).

Zn and gaseous HCl in Et ₂ O or Ac ₂ O in toluene at 0 to 80 ° C. (Todah, Buli. Chem. Soc. Jpn., 45,264,1972) (not for A = NO2).

Level 9e

Zn and aqueous HCl in a suitable solvent (eg EtOH) at 0 to 78 ° C.

In accordance with step 9d above (if A = NO ₂ , it is converted to NH ₂ at the same time). Hydrazine, NaOH in ethane-1,2-diol at 200 ° C (Chemical Abstracts, 74, (1971): 22699) (not for A = COOR, NO ₂ ) or other methods mentioned in J.March above (no for A = COOR, NO ₂ ).

According to Grade 7c (not for A = NO ₂ ).

Reaction Scheme 10 shows pathways to compounds in which W is a valence bond and X is an oxygen atom or a sulfur atom.

SCHEME 10

A = COOAlk, NO ₂ , CH ₃ B = COOH, NH ₂

The rate of lOa

In accordance with step la, but using R ₃ COC1 or (R ₃ CO) ₂ O instead of R ₃ CH ₂ COCl or (R ₃ CH ₂ CO) ₂ O, with or without isolation of the intermediate phenyl ester.

Hexamethylenetetramine in CF ₃ COOH at reflux followed by the addition of aqueous HCl. If A = COOAlk, it can be hydrolyzed to COOH under such strongly acidic conditions and should therefore be re-esterified with appropriate alcohol before the lOc step (eg using thionyl chloride at reflux temperature).

Rate lOb

R ₃ COCH (R ₂ ) Hal in acetone or methyl ethyl ketone or dichloromethane or chloroform in the presence of a suitable base such as K 2 CO 2 NE ₃ or NaH at 20 to 80 ° C.

The rate of lOc

R ₂ CH (Hal) COOAlk in an aprotic solvent, e.g. DMF, in the presence of a base, e.g. 70 ^ Ο ₃ , at 70 to 100 ° C, followed by hydrolysis of crude intermediates with a strong base (e.g. KOH) in a protic solvent such as EtOH at reflux and finally treatment under decarboxylation - dehydration conditions using a non-protic solvent (e.g. xylene) and acid catalyst (e.g. p-toluenesulfonic acid) at reflux or simply heated at 240 ° C in quinoline.

R ₂ CH ₂ Hal and KOH in EtOH at reflux followed by cyclization of isolated intermediate phenyl (thio) ether with sodium methoxide in boiling DMF / MeOH. If A is COOAlk, intermediates (4) can be obtained, where A = COOH.

Using ArCOCH ₂ Br and K ₂ CO ₂ in acetone at reflux, compounds (4) are obtained, wherein R 2 is ArCO.

Rate lOd

Strong mixing in preheated polyphosphoic acid at 90 to 140 ° C. Lewis acid (eg A1C1 ₃ ) in chlorobenzene at 70 to 90 ° C. Cyclizations performed on compounds (3) where R ₃ = C1 with Lewis acid (e.g. A1C1 ₃ ) in o-dichlorobenzene at 45 ° C or with BF ₃ in Et ₂ O at 20 to 25 ° C give compounds (4), where R ₃ = OH, as stated by K. Davies, J. Chem. So. PT 1, 2624, 1957 for compounds in which X = S and R ₂ = H.

The rate of lOe

Sodium alcoholate (1 equivalent) in the same alcohol at 0 to 90 ° C. If A = COOAlk, it may be convenient to use the corresponding AlkOH as the reaction solvent.

If R ₂ = COOAlk and X = S, compounds (4) can be hydrolyzed to the corresponding one

1 ^ 2 = COOH with a mixture of sulfuric and acetic acid (if A = COOAlk is present, A = COOH may also be present), and can be selectively decarboxylated with copper in anhydrous quinoline at 210 to 220 ° C to give compounds (4) , where R ₂ = H, according to J.Cooper et al., J. Chem. Soc. (C) 1971, 3405.

The rate of lOf

R ₂ CH ₂ XH and one equivalent of sodium in EtOH at reflux or with NaHCO ₃ in EtOH mixture: water at 60 to 90 ° C.

The rate of lOg

If A = COO Alk or NO ₂ , the methods described in step lg can be used. It is to be appreciated that the reduction of the NO ₂ group to the NH ₂ group by catalytic hydrogenation can simultaneously lead to the double bond hydrogenation in position 2-3, as indicated by SL Meisel et al., Heterocyclic Compounds, Ed. Interscience Publ .: Compounds with Condensed Thiophene Rings, page 34, (1954) and M. Ahmed, ibid., Ed. Wiley-Interscience: Benzofurans, p. 56, (1974).

If A = NO ₂ and R ₂ = COAr, that the reduction made with hydrogen in the presence of Pt on carbon as a catalyst is 2,3-dihydro compound (5), where B = NH ₂ and R ₂ = CH ₂ Ar, as stated in WO 86/07056.

If A = CH ₃ and R ₂ , R ₃ and R ₆ are not CH ₃ , or R ₂ does not carry the CH ₃ group, the compounds can be converted to the corresponding:

A = CH ₂ Br by reaction with N-bromosuccinimide in CCl ₄ and 2,2'isobisisobutyronitrile or benzoyl peroxide as a catalyst for reflux;

A = CHO by reaction of the above compounds with hexamethylenetetramine in chloroform at reflux, followed by acid hydrolysis of salts in boiling AcOH, or by reaction of compounds where A = CH ₃ with tetrabutylammonium dichromate in chloroform at reflux according to Valenti et al, Arzneim . Forsch., 40,122 (1990);

A = COOH by oxidation of the above compounds (A = CHO) with silver oxide in a mixture of a protic aqueous solvent (e.g. EtOH-DMF at 0 to 70 ° C according to HR Rodriguez et al. Tetrahedron 24, 6587 (1968)) or KMnO ₄ in t-butanol in the presence of aqueous NaH ₂ PO ₄ solution at 70 to 75 ° C according to S. Maruzamo et al., Tetrahedron Letters 27.4537 (1986).

Compounds (4) of the above reaction scheme 10, in which R ₃ = C ₆ H ₅ or t-butyl, R ₂ = H and X = O, can be converted to the corresponding intermediates, where R ₁ is C ₁ H or t-butyl and R ₃ = H, metabolised by polyphosphoric acid at 132 ° C according to Davies et al. J. Chem. Soc., 1958,822.

If X is a nitrogen atom and W has other meanings for which protection is required other than a valence bond, simple starting materials can be prepared according to the following reaction scheme 11.

SCHEME 11

A = COOAJk, N0 ₂

R = H, alkyl

Degree lla

EtOC (R2) = C (COOEt) ₂ at 80 to 140 ° C without solvents or in polar solvent (eg isopropanol).

The rate of llb

R ₂ COC (R ₃ ) COOAlk and p-toluenesulfonic acid or methanesulfonic acid in a chlorinated solvent (eg chloroform or dichloromethane) or an aprotic solvent (eg benzene) under reflux under azeotropic conditions.

Rate of lic

Heating in Ph ₂ O in the presence of p-toluenesulfonic acid or phosphoric acid or ZnO as catalysts at 245-255 ° C according to Hung. Teljies 6251 (Chemical Abstracts, 79,92026v, 1973).

Heating in a high boiling solvent (e.g. Ph ₂ O) followed by hydrolysis of uninsulated compounds (4) (R ₃ = COOEt) with a strong acid (e.g. HCl) in a protic solvent (e.g. acetic acid) at reflux, that compounds (IV) are obtained wherein R ₃ = COOH. The above isolated compounds can be decarboxylated by heating in a high boiling solvent (e.g., Ph ₂ O) to give compounds (4) where R ₃ = H, according to R. Albrecht et al. Ber. 105.3118 (1972).

The rate of lld

Heating in a high boiling solvent (eg Ph ₂ O) at 255 ° C.

If R = Alk, the compounds (4) are obtained directly from the compounds (1) without isolation of the compounds (3) by condensation with R ₂ COCH (R ₃ ) COOAlk in polyphosphonic acid at 90 to 150 ° C according to F. Piozzi et al., Gazz. Chim. It., 100,678,1970.

Degree Ile

Amalgan Al / Hg in aqueous EtOH solution at reflux, followed by acidification with strong acid (e.g. HCl) and treatment with FeCl ₃ at reflux according to WA Denny et al., J. Med. Chem., 32,396,1989.

If A = COOAlk, the compounds (4) must be hydrolyzed to the corresponding A = COOH prior to performing the Ile step.

If A = NO ₂ , then intermediates (5) are obtained, where A = NH2 ·

The rate of llf

R2CH = CHCHO and arsenic acid in a strongly acidic medium (eg concentrated H ₂ SO ₄ ) and kept at 105 to 115 ° C according to EP 0206802.

If A = COOAlk, compounds (1) must be hydrolyzed to the corresponding A = COOH prior to step f. All compounds (1) have R = H and the resulting compounds (5) have R ₃ = H.

The rate of leagues

R2CH (Hal) -CH (R ₃ ) COOH in a protic solvent (e.g. water) in the presence of a strong base such as NaOH at 100 to 125 ° C, followed by cyclization of the isolated compounds of / 3-anilinopropionic acids with pre-heated polyphosphoric acid acid at 120 to 125 ° C, or with phosphorus pentoxide in aprotic solvent with high boiling point (eg xylene) at 120 to 140 ° C. In some cases it is advantageous to proceed from compounds (1) wherein R = tosyl or other suitable protecting groups; the resulting compounds (6), where R = tosyl, can be easily converted to compounds (6) where R = H by hydrolysis with strong acid (e.g. HCl) in a protic solvent (e.g. AcOH) at reflux.

If A = COOAlk, compounds (6) are obtained, where A = COOH.

Interest rate

R ₂ CHO and ethylene in AcOH and HCl at 25 to 30 ° C according to KD Hesse, Liebigs Ann. Chem. 741, 117 (1970). If in compounds (1) R = H, the starting materials (7) are obtained, where R = R ₃ = H.

Epichlorohydrin followed by cyclization of isolated anilinopropanol derivatives in Ν, diet-diethylaniline or o-dichlorobenzene at reflux in the presence of proton acceptor (e.g. NEt ₃ ) according to SD Boyd et al., J. Org. Chem. 30, 2801 (1965). In this case, compounds (7) are obtained, where R = R2 = H and R ₃ = OH.

The rate of lli

By hydrogenation in the presence of a catalyst (e.g. platinum oxide) in a protic solvent (e.g. EtOH) at 20 to 30 ° C and 1.96 to 3.92 bar according to

GM Coppolo, J. Heter. Chem. 15, 645, 1978. If A = NO ₂ , compounds (7) are obtained, where A = NH ₂ .

The compounds (4), (6) and (7) thus obtained can be converted to the corresponding derivatives according to the methods of reaction scheme 1, step lg, where A = COOH or NH,.

The synthesis of the simple compounds (7) from reaction scheme 11, where R = H and A = COOH, can also be carried out using the method shown in reaction scheme 12.

SCHEME 12

W = CH ₂ or bond

Level 12a

Oxalyl chloride in polar solvent (eg THF) at reflux, followed by internal Friedel-Crafts acylation of crude chlorooxalylamide with Lewis acid (e.g. A1C1 ₃ ) in a non-polar solvent (e.g. CS ₂ ) at reflux according to EP 0402859.

Step 12b to 35% aqueous H ₂ O ₂ and a strong base (e.g. NaOH) in a polar solvent (e.g. water) at 20 to 30 ° C, followed by the addition of a strong acid (e.g. HCI) as indicated in EP 0402859.

Reaction schemes 13 and 14 lead to simple starting materials in which X represents an imino group and W represents a valence bond. In these two reaction schemes, A has the same meanings as in reaction scheme 1.

SCHEME 13

Level 13a

C1CH ₂ C (C1) = CH ₂ in the presence of K ^ COg at 40 to 80 ° C according to L. Purdie, J. Chem. Soc. (C) 1970,1126.

Level 13b

RgCOHal in pyridine or chlorinated solvent (eg dichloromethane) in the presence of a proton acceptor (eg NEt ₃ ) at 20 to 100 ° C, or in a polar solvent (eg acetone) in the presence of KjCOg at 20 to 80 ° C.

Level 13c

BF ₃ in MeOH at 130 to 155 ° C; heating at 100 to 110 ° C.

In compounds (5) obtained with step 13c, R _{2 is} always CH ₃ .

Level 13d

R ₂ COCH (OAlk) ₂ in a non-polar solvent (eg toluene) in the presence of iodine as a catalyst for reflux under azeotropic conditions, followed by reduction of an isolated (or uninsulated) imino compound with NaBH ₄ in a polar solvent (eg MeOH) in the presence of NaOH as a catalyst for reflux. If A = COOAlk, it will hydrolyze into COOH.

Level 13e

Sodium amide in a high boiling solvent (e.g., Ν, Ν-diethylaniline) at 220 to 250 ° C according to F. Piozzi et al., Gazz. Chim. It., 93.1382,1963.

Potassium t-butoxide in polar solvent (eg DMF) at 20 to 100 ° C according to EP 0042298.

Level 13f

BF ₃ in apolar solvent (eg benzene) at 5 to 10 ° C.

Rate 13g

Zn or Fe powder in an acidic medium (eg AcOH) and water at 70 to 100 ° C. If A = NO ₂ , it will be reduced to NH ₂ .

The rate is 1pm

Thionyl chloride at reflux. The resulting acyl chlorides are isolated and reacted with sodium azide in acidic medium (eg AcOH) at 10 to 20 ° C and then heated to 50 to 70 ° C.

Level 13i

Diazotization with NaNO ₂ in concentrated H ₂ SO ₄ followed by the addition of aqueous ZnCl ₂ at 5 to 10 ° C and the metabolism of isolated diazonium salts with CH ₂ -C (R ₂ ) COOH in a polar solvent (eg acetone) in the presence of copper salt (e.g. CuCl ₂ ) at 25 to 30 ° C. Examples of grades 13g, 13h and 13i are cited by A. Allais et al., Eur. J. Med. Chem., 10,187.1975.

Level 13j

R ₂ CH ₂ NO ₂ in a polar solvent (e.g. EtOH) in the presence of a base (e.g. n-butylamine) and catalytic amounts of acid (e.g. AcOH) at reflux.

The compounds (5) thus obtained can be converted to the corresponding derivatives, where A = COOH or NH ₂ , according to the methods of reaction scheme 1, step lg.

With reference to reaction scheme 14, it is intended that the compounds (4), where R ₃ = H, correspond to the compounds (5) of reaction scheme 13.

SCHEME 14

R = alkyl

Level 14a

NaNO ₂ in aqueous acidic medium (eg HCl) at -5 to +5 ° C.

Isoamyl nitrite in a polar solvent (eg EtOH) at 5 to 10 ° C.

Level 14b

An aqueous solution of SO ₂ at 0 to 10 ° C according to Pfannstiel et al., Ber. 75, 1096, 1942.

Triphenylphosphine and heating of isolated phosphonium salt in aqueous-alcoholic HCl solution at reflux according to Homer et al., Ber. 85,1073,1953.

Level 14c

R ₂ COCH (R ₃ ) Hal in a high boiling base solvent (eg N, Ndiethylaniline) at 160 to 180 ° C or by simple heating without solvents at 180 ° C.

R ₃ COCH (R ₂ ) Hal in polar solvent (eg acetone) in the presence of a suitable proton acceptor (eg K ^ CC ^) at reflux, followed by cyclization of isolated β-anilinoketone intermediates with freshly melted ZnCl ₂ in a protic solvent (EtOH ) at reflux.

R2CH (Hal) CN in the presence of BC1 ₃ and Lewis acid (e.g. TiCl ₄ ) in a non-polar solvent (e.g. benzene) at reflux, followed by cyclization of the isolated 2 amino- haloacetophenones. Compounds with a suitable reducing agent (e.g. NaBH ₄ ) in polar media (e.g. dioxane-water) at reflux according to T. Sagusawo et al., J. Org. Chem., 44, 578, 1979. Compounds (4) are obtained by the above method, where R ₃ = H.

R ₂ COCH (R ₃ ) Hal (half equivalent) in polar solvent (eg MeOH) at reflux, followed by cyclization of isolated intermediates of Schiff bases with strong acid (eg CF ₃ COOH) at 20 to 30 ° C.

Level 14d

R ₂ COCH ₂ R ₃ by heating at 100 ° C without solvents or at reflux in a polar solvent (eg MeOH), followed by cyclization of isolated hydrazone compounds with polyphosphoic acid at 100 to 130 ° C, or by simple heating into ethylene glycol or aqueous formic acid or ethanol formic acid.

The cyclization can also be carried out by heating in ethanol HCl at reflux or in an AcOH / HCl mixture at reflux or in orthophosphoic acid at 95 to 105 ° C or by simple heating with anhydrous ZnCl ₂ at 100 to 220 ° C. If A = COOAlk, compounds (4) can be obtained, where A = COOH.

Level 14e

Borane-pyridine complex at 0 to 30 ° C, followed by the addition of a protonation agent (eg HCl).

Tin or zinc and aqueous HCl at 50 to 100 ° C.

NaBH ₄ in the presence of Lewis acid (e.g. A1C1 ₃ ) in pyridine at 0 to 30 ° C or alternatively in the presence of salts such as cobalt or zinc chloride.

Sodium borocyanohydride in AcOH at 20 to 80 ° C.

Hydrogen in the presence of a catalyst (eg Pt) in a polar solvent (eg EtOH) at 20 to 80 ° C.

Other general methods are cited by Houlihan in Heterocyclic Compounds, part one, Ed. Wiley-Interscience: Indoles, p. 462 (1972). If A = NO ₂ , compounds (4) can be reduced to the corresponding compounds (5) where A = NH2.

Level 14f

NaH and RHal in anhydrous polar solvent (eg DMF) at 20 to 80 ° C. RHal in the presence of potassium carbonate in a polar solvent (eg acetone) at reflux.

Sodium amide and RHal in a polar anhydrous solvent (eg THF) at low temperature (-70 ° C).

Compounds (4) having other reactive groups, such as NH ₂ or OH, should be protected using suitable protecting groups that can be selectively cleaved at the end by methods of deprotection.

Degree 14g

RHal in the presence of alkali metal carbonates (e.g., potassium carbonate), as stated by Houlihan in Heterocyclic Compounds, part two, Ed. WileyInterscience: Indoles, page 90 (1972), and references cited therein.

Compounds (5) having other reactive groups than NH ₂ or OH should be protected as indicated above.

Grade 14h

Tetrachloro- [1,4] benzoquinone in polar solvent (eg ethylene glycol monomethyl ether) at reflux.

Copper (II) chloride in pyridine at reflux according to Kikugawo et al. J. Heter. Chem., 16, 1325, 1979.

Compounds (6) where R ₂ and R _{3 are} different from H can be reduced to the corresponding starting materials (7) with lithium aluminum hydride according to HC Printy et al., J. Am. Chem. Soc., 71,3206,1949.

Compounds (4) of reaction scheme 14, where R ₂ = H and R ₃ = OH, can be obtained from compounds (7) of reaction scheme 11, where R = R2 = H and R ₃ = OH, by shrinking the ring at using an oxidant (e.g., sodium peiodate) and base (e.g., NaOH) in aqueous EtOH at reflux according to SD Boyd et al., J. Org. Chem., 30,2801,1965.

The starting materials (4), (5), (6) and (7) can be converted to the corresponding A = COOH or NH ₂ by the method of reaction scheme 1, step lg, and from them to alternative end products. If NH is present and could interfere with the following reactions, it can be protected as stated by TW Green in Protective Groups and Organic Synthesis, Wiley Interscience, 1981. Alternatively, non-reactive groups (e.g., NOJ can be converted to reactive (e.g., NHJ as a final stage in paths.

Starting materials in which W is a valence bond, X is an imine group and the 7-substituent is a carboxymethyl group can be obtained according to reaction scheme 15.

SCHEME 15

Ηοοσ

Level 15a

Hydrogen in the presence of 10% Pd / C as a catalyst at 20 bar in water containing 1 equivalent of NaOH, followed by diazotization with sodium nitrite in HCl at 0 to 5 ° C and tin chloride. Cyclization is carried out during acidification of the tin salt with H ₂ S and completed by refluxing in xylene, see HE Baumgarten et al., J. Am. Chem. Soc., 82,3977,1960.

Level 15b

RgCH ^ COR ^ in the presence of an acid (e.g. acetic acid) in a polar solvent (e.g. EtOH) at reflux as indicated by WJ. Welstead et al., J. Med.Chem., 22,1074 (1979) for R ₂ = CH ₃ and R ₃ = C ₆ H ₅ , where steps 15c and 15d are also indicated.

Level 15c

Lower alkanol (e.g. MeOH, EtOH) at reflux in the presence of hydrogen chloride flow. Level 15d

Strong base (eg KOH) in a polar solvent (eg water) at reflux.

The preparation of simple starting materials where R ₃ = hydroxyalkyl and / or the corresponding ethers can be carried out by reacting either compounds (3) from reaction scheme 1, compounds (2), (4) or (5) from reaction scheme 2 , compounds (4) of reaction schemes 6, 10, 11 and 15, compounds (5) of reaction scheme 13 and compounds (4) and (6) of reaction scheme 14, where R ₃ = H, CH ₃ , respectively by reaction scheme 16, wherein A and B have the same meanings as in reaction scheme 1, R ₄ represents an alkyl or aralkyl group and R ₅ represents H or an alkyl group.

SCHEME 16

\

j

R ₄ = Alk, aralkyl R ₅ = H, Alk

Level 16a

R ₃ = H, W = CO, CS (and no activated phenyl ring is present):

Formaldehyde and HCl in water, EtOH or AcOH at 50 to 100 ° C.

Chloromethyl methyl ether and fuming sulfuric acid at 50 to 70 ° C (H. Nakarumo et al., Buli. Chem. Soc. Jap., 57,2323,1984).

R ₃ = CH ₃ , W = CO, CS, bond, and there are no other methyl groups in the molecule:

N-bromosuccinimide in the presence of benzoyl peroxide or 2,2'-azobisisobutyronitrile in CC1 ₄ at 50 to 80 ° C.

Level 16b

R ₃ = H, W = bond, X = O, S, NH or N-Alk and no other electron donating groups are present on the other rings of the molecule:

Phosphorus oxychloride and DMF at 50 to 140 ° C or other Vilsmeyer - Haack reagents (see Jutz, Adv. Org. Chem., 9,225,1976).

R ₃ = CH ₃ , W = bond, X = O, S, NH or N-Alk and no other CH ₃ groups are present: Irradiation with a high-pressure mercury lamp in a protic solvent (e.g. AcOH) at 20 to 100 ° C. as cited by Frasca et al., Tetrahedron, 23, 603, 1973.

Level 16c

Sodium or potassium acetate in aprotic solvents (eg acetone, DMF) at 40 to 120 ° C.

I

Level 16d

R ₅ in compounds (5) = H:

Reducing hydride (eg NaBH ₄ ) in a polar solvent (eg MeOH or EtOH or dioxane) at 0 to 80 ° C.

R ₅ in compounds (5) = alkyl:

Alkyl magnesium bromide in aprotic solvents (eg Et ₂ O, THF) at 0 to 60 ° C.

Level 16e

NaOH or LiOH in protic solvents (eg alcohols, water) or mixtures thereof at 25 to 50 ° C. (In this case, if A = COO Alk, it will hydrolyse to COOH at the same time).

Level 16f

Same methods as in step lg of reaction scheme 1 but oxidation of CH = CHCH ₃ in COOH for compounds (5).

Rate 16g

Strong base (e.g. NaH) and reagent R ₄ -L (where L is a halogen atom or tosyloxy group) in anhydrous aprotic solvents (e.g. DMF or THF) at 20 to 140 ° C.

The rate is 4pm

R ₄ OH and base (e.g. Na, NaH) in excess of R ₄ OH or in aprotic solvents (eg DMF or THF) at 20 to 140 ° C.

The simple compounds (6) having the hydroxyalkyl group in position 3 thus obtained can be metabolized as such or alternatively derivatized on the hydroxymethyl group by known reagents and methods, so that this group does not interfere with the further reaction steps necessary to prepare those compounds of formula (I) bearing a protected hydroxy alkyl group such as R _y

The protected end compounds are finally converted by the deprotection methods to the compounds of formula (I), wherein R ₃ = hydroxyalkyl.

The prodrugs as defined above can be prepared from the corresponding hydroxy compounds according to method 1 below or from the corresponding amide compounds according to method 2 below.

Method 1

By metabolism with chloroformate, isocyanate or isothiocyanate, carbonyl chloride or bromide or other activated acid derivative (eg anhydride) in a suitable solvent (eg chlorinated solvent, DMF, THF, dioxane, acetonitrile, pyridine) in the presence or absence of a base (e.g. NEt ₃ , pyridine, 4-dimethylaminopyridine, NaOH, potassium carbonate or 1,10-diazabicyclooundecene or other not specifically mentioned) at -20/100 ° C.

By carboxylic acid metabolism in the same solvents as above in the presence of a condensing agent such as Ν, Ν′-carbonyldiimidazole, carbodiimides or others known in the art.

By metabolism with dialkyl or diaryl chlorophosphate or dialkyl cyanophosphonate under the same conditions as described above (for examples of such derivatization methods see Example 114 below and S.O. Thorberg et al., J. Med. Chem., 30.2008,1987.

Method 2

The prodrug derivatives of the acidic NH groups according to the chapter The compounds of the invention can be synthesized from the compounds of formula I discussed in this chapter by preparing an N-hydroxy (substituted) methyl derivative and reacting it under exactly the same conditions, as described above for oxygen derivatization.

Intermediates The N-hydroxy (substituted) methyl derivative can be isolated or directly digested to give the desired compound. N-hydroxy (substituted) methyl derivatives of the Ny-CH (R ₁ ) OH type, where R is _X = H or CC1 ₃ , can be obtained by reacting suitable compounds of formula I with formaldehyde or CC1 ₃ CHO, as described in HE Zaugg, Organic Reactions, 14, Chapter 2, 52 J. Wiley and Sons New York, 1965 or in JP Chupp, J. Org. Chem., 28, 2592, 1965.

If R _x = phenyl, these compounds can be synthesized by reaction with benzaldehyde and cyclic amine (e.g. morpholine) in MeOH or dichloromethane / MeOH 1: 1 at 0 ° C to reflux and hydrolysis of the intermediate with 0.1 N HCl at pH 4. (O. Jacobseen, Annalen, 157, 243,1884; H. Bundgaard et al. Int. J. Pharm., 22, 45,1984).

All reaction routes and steps described above are intended to be exemplary and do not limit the scope of the invention. It will be appreciated by those skilled in the art that we perform these chemical transformations on polyfunctional substrates and that the reagents used may be disrupted as they will also react with other groups present in the molecules. For example, catalytic hydrogenation may convert nitro groups to amino groups as desired, but hydrogenation of the individual double bonds and removal of halogen atoms may also occur. Lithium aluminum hydride can reduce conjugated ketones to alkanes as desired (eg step 7c in reaction scheme 7), but can also include COO Alk groups in CH ₂ OH or NO ₂ groups in -N = N- etc. Unwanted side reactions can be avoided or minimized by choosing the right conditions or by using alternative reagents or other synthesis routes. To give negative results to this alternative approach, the undesired intermediates obtained must be converted into useful ones using methods known to those skilled in the art.

DETAILED PREPARATION OF INTERMEDIATES

8- (3-Bromopropoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

Dg of 1,3-dibromopropane was added dropwise at room temperature to a suspension of 30 g of sodium 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water. The reaction mixture was stirred at room temperature for 5 days. 100 ml of water were added and stirring continued for 15 minutes. The precipitate was filtered off by suction, washed with water and purified by flash chromatography on silica gel, eluting with chloroform: ethyl acetate 95: 5. The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p. 114 to 115 ° C.

The benzopyran carboxylate salt used in the above synthesis was prepared by dissolving 104 g of the corresponding acid in 560 ml of hot methanol and adding 280 ml of an aqueous solution of 31 g of sodium hydrogen carbonate. 850 ml of acetone was added to the solution to precipitate the desired salt, which was collected by suction filtration (62 g, mp> 280 ° C). The corresponding acid was prepared according to Da Re, P. et al., J. Med. Pharm. Chem., 2,263.1960.

8-hydroxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate II)

467 ml of 1.48N sodium borohydride solution in anhydrous dimethylformamide were added over 30 minutes while stirring at room temperature to a solution of 100 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 11 anhydrous dimethylformamide. The reaction mixture was stirred for 2 V2 hours at room temperature. 88 ml of 2 N hydrochloric acid were added while maintaining the temperature at 0 to 5 ° C. Then 102 ml of 12.7 N sodium hydroxide solution were added. The mixture was poured into 61 water, stirred for 3 hours and filtered through a Buchner funnel. The filter cake was washed with 4 N sodium hydroxide solution and then with water. The resulting white solid was crystallized from methanol to give 50 g of the title compound, mp 145 to 147 ° C.

E-8- (2-carboxyvinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate III)

A mixture of 7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Uneyama, K. et al., Buli. Chem. Soc. Jap., 58, 2361,1985), 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml of anhydrous pyridine were stirred at 100 ° C for 3 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into a mixture of 90 g of crushed ice and 33 ml of hydrochloric acid (d = 1.18). The resulting precipitate was collected by suction filtration, washed with water and crystallized twice from 95% ethanol to give

5.5 g of the title compound, m.p. 226-229 ° C.

E-8- (2-Chlorocarbonylvinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate IV)

A solution of 9.2 g of intermediate III and 7.8 g of thionyl chloride in 75 ml of toluene was refluxed for 3 hours. After cooling to 20 to 25 ° C, the resulting crystals were collected by suction filtration, washed with acetone and dried in vacuo to give 6.8 g of the title compound, m.p. (190) 196 to 198 ° C after recrystallization from toluene.

8-acetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate V)

1.17 g of magnesium filings, 7.4 ml of anhydrous ethanol and 0.2 ml of anhydrous carbon tetrachloride were placed under a round-bottomed nitrogen stream. When the temperature started to rise, 7.5 ml of anhydrous chlorobenzene was added, followed by a slow drop (25 minutes) solution of 5.28 ml of anhydrous diethyl malonate and 3.5 ml of anhydrous chlorobenzene in 16 ml of anhydrous ethanol. The reaction flask was heated to 75 ° C for 2 hours, cooled to 25 ° C and slowly added, without exceeding 35 ° C, a solution of 8.8 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran -8-carbonyl chloride in 88 ml of anhydrous chlorobenzene. The reaction mixture was stirred for 2 hours at 35 ° C and then cooled to 0 ° C. 13 ml of water and 1.9 ml of sulfuric acid (d = 1.84) were added. The resulting solution was decanted from insoluble inorganic substances and the volatiles were expelled in vacuo.

The crude acylmalonate obtained was refluxed for 6 hours with 10.4 ml of acetic acid, 7 ml of water and 1.3 ml of sulfuric acid (d = 1.84). After cooling, the solution was poured into ice water and the precipitate was collected by suction filtration and washed with aqueous sodium carbonate. Crystallization from 90% ethanol gave 6.5 g of the title compound, m.p. 159161 ° C.

8-Bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate VI)

A solution of 11.2 g of bromine in 250 ml of chloroform was added over a period of 2 hours at 20 to 25 ° C to a solution of 19.5 g of intermediate V in 700 ml of chloroform. After stirring at 20 to 25 ° C for 1 hour, the solution was washed with 400 ml of 2N aqueous sodium hydroxide solution and then repeatedly with water, dried with anhydrous sodium sulfate and the volatiles removed in vacuo. The crude product was treated with diethyl ether, collected by suction filtration and crystallized from acetone to give 16 g of the title compound, m.p. 134-135 ° C.

8- (2-Hydroxyethylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran flermediate

VII)

The title compound was prepared in the same manner as intermediate XXXVI except that 2-aminoethanol was used instead of 3-aminopropanol. Tal. Mp 206-208 ° C.

3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonyl chloride (Intermediate VIII)

A solution of 4.55 g of sodium nitrite in 12 ml of water was added dropwise while stirring to a mixture of 15.1 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re, P. et al., Farmaco II (Ed. Sci.), 11, 670, 1956] in 150 ml of hydrochloric acid (d = 1.18) at -5 ° C. Stirring was continued at 0 30 minutes The solution was poured over 10 minutes and at -5 to 0 ° C in 120 ml of a 30% by weight sulfur dioxide solution in acetic acid containing 1.53 g of copper (II) dihydrate chloride and 13 ml of water After 1 hour at 0 ° C and 1 hour at 20 to 25 ° C, 300 ml of ice water was added to the mixture and a precipitate formed which was collected by suction filtration, washed with water and dried in exicato over sodium hydroxide to constant weight to give 18 g of the crude title product, mp 165 to 170 ° C, for use without further purification.

8- (3-chloropropoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate IX)

This compound was prepared in the same manner as intermediate XI except that 1-bromo-3-chloropropane was used instead of 1-bromo-2-chloroethane. Tal. 98 to 102 ° C after washing with petroleum ether: diethyl ether 7: 3.

8-Acrylamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate X)

A solution of 1.75 ml of acryloyl chloride in 15 ml of anhydrous tetrahydrofuran was added dropwise 5 g of 8-amino-3-methyl-4-oxo-2-phenyl4H-1-benzopyran and 3 ml of triethylamine while stirring at -10 ° C. in 60 ml of anhydrous tetrahydrofuran. After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the reaction mixture was poured into water and filtered by suction. The filter cake was washed with water. Drying afforded 5.5 g of a sat. 229-230 ° C.

8- (2-Chloroethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XI)

A mixture of 7.52 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re, P. et al., Ann. Chim., 1962, p. 506 ff), 6.22 g of anhydrous potassium carbonate and 25.5 ml of l-bromo-2-chloroethane in 70 ml of dimethylformamide were stirred at 60 ° C for 25 hours. The mixture was cooled to 20 to 25 ° C and poured into 600 ml of water. The organic solution obtained by extraction with dichloromethane was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents and excess l-bromo-2-chloroethane were evaporated in vacuo to give 8.8 g of the title compound, m.p. 141 to 142 ° C after crystallization from chloroform: hexane.

8- (2-Azidoethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XII)

A mixture of 15.2 g of intermediate XI and 6.24 g of sodium azide in 150 ml of anhydrous dimethylformamide was stirred at 70 to 75 ° C for 12 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 1½ liters of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents were evaporated in vacuo. The residue was taken up in water, collected by suction filtration and dried to give 14 g of the title compound, soil. 119-120 ° C.

8- [N- (2-Hydroxyethyl) -N-methyl-carbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XIII)

A solution of 1.6 ml of 2-methylamino-ethanol in 10 ml of water was added dropwise over 5 minutes to a suspension of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and

1.52 g of potassium carbonate in 60 ml of acetone. After stirring for 2 do hours at 20 to 25 ° C, the solvent was removed in vacuo and the residue was taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes and then filtered. The solvent was evaporated from the filtrate and the residue was dissolved in 20 ml of dimethylformamide, treated with 14 ml of a 1.4% sodium carbonate solution, stirred for 30 minutes at 20 to 25 ° C and diluted with 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5 N hydrochloric acid and then with water. The solution was dried over anhydrous sodium sulfate and the chloroform evaporated. The resulting oil was taken up in 200 ml of diethyl ether and stirred for 2 hours at 20 to 25 ° C. The solids were collected by filtration and crystallized from ethyl acetate to give 4.97 g of the title compound, m.p. 128-130 ° C.

8- (2-Chloroethylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XIV)

The title compound was prepared in the same manner as intermediate XXXVII except that intermediate VII was used instead of intermediate XXXVI and the reaction was carried out at room temperature. Tal. 181-182 ° C (ethyl acetate).

8- (N-methyl-2-chloro-ethylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XV)

A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane was added to a solution of 3.37 g of intermediate XX in 20 ml of dichloromethane and the mixture was stirred for 4 hours at room temperature. Removal of the solvent gave an oil which was taken up in diethyl ether. The title compound precipitated as a white solid, which was collected by filtration for use without further purification. Tal. (118) 126-128 ° C (diethyl ether).

8- (4-Bromobutoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVI)

A mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in 45 ml of dimethylformamide was stirred at 75 ° C for 2 hours. The mixture was cooled to 20 to 25 ° C, poured into 100 ml of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents and excess 1,4dibromobutane were evaporated in vacuo. The residue was washed with 55 ml of petroleum ether: diethyl ether 7: 4 and collected by suction filtration to give 5.6 g of the title compound, m.p. 91 to 92 ° C.

8- (5-Bromopentyloxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVII)

This compound was prepared by the method described for the preparation of intermediate XVI, except that 1,5-dibromopentane instead of 1,4-dibromobutane was used and the crude product was purified by column chromatography on silica gel (elution with dichloromethane: ethyl acetate 99: 1). Tal. 75 to 76 ° C, after washing with petroleum ether: diethyl ether 30: 4.

8- (2-Chloroethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVIII) ml of thionyl chloride in 18 ml of chloroform was added at 0 ° C while stirring to a solution of 23 g of intermediate XXII and 11 ml of triethylamine in 185 ml of chloroform. The reaction mixture was heated to 70 ° C and stirred for 2 hours. After cooling to room temperature, it was poured into water. The organic layer was separated, washed with sodium chloride solution, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. Yield: 24 g of the title compound. The sample crystallized from ethanol had a melting point of 102 to 103 ° C.

8-Chloromethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XIX)

53.4 g of intermediate II and 38.8 ml of anhydrous triethylamine were dissolved in 440 ml of chloroform. A solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous chloroform was added to this solution, which was maintained at -10 to -2 ° C. The reaction mixture was stirred at room temperature for 4 hours and then diluted with 400 ml of water. The aqueous phase was extracted with chloroform and the extracts were added to the chloroform phase. The chloroform solution was washed with brine, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. Yield: 56 g of the title compound having a melting point of 112 to 113 ° C after recrystallization from ethanol.

8-Methylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XX)

A solution of 15.1 g of anhydrous zinc chloride and 14.5 g of sodium cyanoborohydride in 400 ml of anhydrous methanol was added dropwise at 0 ° C while stirring to a mixture of 58.8 g of 8-formyl-3-methyl-4-oxo-2- phenyl-4H-1-benzopyran, 60.7 g methylamine hydrochloride and 125 ml triethylamine in 600 ml anhydrous methanol. After stirring for 5 hours at 20 to 25 ° C, the solvent was evaporated in vacuo and the residue was taken up in 200 ml of water and collected by suction filtration. The crude product was dissolved in aqueous acetic acid, washed with ethyl acetate and re-precipitated by the addition of a cold solution of 6 N sodium hydroxide. 49 g of the title compound are obtained. Tal. 97 to 99 ° C after recrystallization from 75% ethanol.

8- (2-Chloroethylthiomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXI)

A solution of 37 g of intermediate XIX and 10.5 g of thiourea in 370 ml of ethanol was refluxed for 1 hour. The reaction mixture was cooled to room temperature and 42 g of 8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran were crystallized spontaneously. The ethanol recrystallized sample had a melting point of 233 to 235 ° C.

ml of 35% aqueous sodium hydroxide solution was added while vigorously stirring to a suspension of 35 g of the compound thus prepared and 1.05 g of benzyl triethylammonium chloride in 440 ml of 1,2-dichloroethane. The mixture was stirred for 2½ hours and then poured into 300 ml of water. The aqueous layer was extracted with 1,2-dichloroethane and the extracts were added to the organic layer, which was washed with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was crystallized from methanol to give 22 g of the title compound, m.p. 82-83 ° C.

8- (2-hydroxyethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

XXII)

A solution of 2.5 g of intermediate XIX in 25 ml of xylene and 3 ml of dioxane was prepared. 0.15 g of sodium was dissolved in 3.10 ml of anhydrous ethylene glycol and this solution was added dropwise at room temperature to a solution of intermediate XIX. After 5 hours of reflux, the reaction mixture was cooled to room temperature and poured into 50 ml of water. It was extracted with dichloromethane and the extract was washed with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The solid residue was crystallized from ethanol to give 2.1 g of the title compound, m.p. 132-133 ° C.

8-Trifluoroacetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIII)

A solution of 9.5 ml of trifluoroacetic acid anhydride in 20 ml of anhydrous dichloromethane was added dropwise at -5 to 0 ° C to a solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 50 ml. anhydrous dichloromethane. The reaction mixture was stirred for 2 hours at 20 to 25 ° C and then poured onto crushed ice. The organic solution obtained by extraction with dichloromethane was washed with cold 5% aqueous sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was crystallized from ethanol to give 5.2 g of the title compound, m.p. 175-176 ° C.

8-Aminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIV)

A mixture of 21 g of intermediate XXIX and 19 g of triphenylphosphine in 160 ml of tetrahydrofuran was stirred at room temperature for 8 hours. Thin layer chromatography showed the disappearance of intermediate XXIX. 3 ml of water were added and stirring continued for 24 hours. The solvents were removed on a rotary evaporator and the residue was dissolved in water as acetate. The aqueous solution was washed with ethyl acetate, basified with 37% sodium hydroxide solution and filtered on a Buchnet funnel. The filter cake was washed with water and dried to give 18 g of the title compound. The hydrochloride recrystallized from ethanol had a melting point of 256-258 ° C.

8- (2-Chloroethylsulfonylmethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

XXV)

41.6 ml of aqueous 30% hydrogen peroxide were added dropwise at 40 ° C over a period of 20 minutes to a solution of 26.2 g of intermediate XXI in 300 ml of glacial acetic acid. The mixture was heated to 60 ° C, stirred at this temperature for 4½ hours, cooled to room temperature and poured into 60 ml of water. Filtration on a Buchner funnel gave a filter cake which was washed with water and dried to give 29.4 g of the title compound. The sample was crystallized from ethanol. Tal. (89) 159-161 ° C.

8- (2-Chloroethylsulfinylmethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

XXVI) ml of aqueous 30% hydrogen peroxide was quickly added dropwise at 10 ° C to a solution of 12 g of intermediate XXI in 84 ml of glacial acetic acid. The reaction mixture was stirred for 4 hours at room temperature and then poured into 220 ml of water. The title compound was collected by suction filtration, washed with water and dried. Yield: 12.4 g, m.p. 142-145 ° C (methanol).

8- [N-methyl-N- (2-chloroethyl) -aminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXVII)

A mixture of 22 g of intermediate XX, 66 ml of 1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide was stirred at 20 to 25 ° C for 12 hours. The reaction mixture was then poured into 600 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and acidified with ethanol. The solvent and excess l-bromo-2-chloroethane were distilled off in vacuo at 70 to 80 ° C. The residue was taken up in cold IN aqueous sodium hydroxide solution and extracted with dichloromethane. The organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo at 25 to 30 ° C. The crude title product was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 7: 3 to give 18 g of the title compound, which melted at 118-120 ° C after crystallization from ethanol.

1- (2-hydroxy-2-methylpropyl) -4- (2-methoxyphenyl) -piperazine (Intermediate XXVIII)

A mixture of 7 g of 1- (2-methoxyphenyl) -piperazine, 7.33 g of anhydrous potassium carbonate, 1.75 g of potassium iodide and 5.6 ml of l-chloro-2-methyl-2-propanol was stirred for 90 minutes at 70 ° C and then for another 6 hours at 90 ° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The title product was obtained as an oil and was characterized as its dihydrochloride, which, crystallized from ethanol, melted at 225 to 227 ° C.

8-Azidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIX)

A mixture of 22.8 g of intermediate XIX and 6.8 g of sodium azide in 110 ml of dimethylformamide was stirred for 3 hours at 100 ° C. After cooling to room temperature, 130 ml of water and 88 ml of ethanol were added to the reaction mixture. After 1 hour, the crystals were collected by vacuum filtration, washed with water and dried. Yield: 22 g of the title product. The ethanol recrystallized sample had a melting point of 132 to 134 ° C.

8- [N- (2-Hydroxyethyl) -aminomethyl1-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXX)

A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of sodium cyanoborohydride in 71 ml of anhydrous methanol was added dropwise 9.24 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H- under stirring. l-benzopyran and 9.12 g ethanolamine in 90 ml anhydrous methanol. Stirring was continued at 20 to 25 ° C for 5 hours before the solvent was removed in vacuo. 250 ml of water were added to the residue and the insolubles were collected by suction filtration and washed with water. The crude product was dissolved in 1 N acetic acid and the solution was washed with ethyl acetate. The aqueous solution was then basified by addition of 2N sodium hydroxide solution and the precipitate was collected by suction filtration and washed with water to give 8.5 g of the title compound, m.p. 117 to 121 ° C after drying at 60 ° C.

8- (N-methyl-N-chloroacetyl-aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXI)

A solution of 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane was added dropwise at -5 to 0 ° C to a solution of 20 g of intermediate XX and 10 ml of triethylamine in 200 ml of 1,2 dichloroethane. After stirring at 20 to 25 ° C for 2 hours, 150 ml of water were added to the reaction mixture and the phase was separated. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was crystallized from ethanol to give 22.5 g of the title compound, m.p. 146 to 148 ° C.

8-Chloroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXII)

A solution of 3.2 ml of chloroacetyl chloride in 32 ml of 1,2-dichloroethane was added dropwise at -5 ° C while stirring to a mixture of 10 g of intermediate XXIV and 5.5 ml of triethylamine in 80 ml of 1,2-dichloroethane. The reaction mixture was stirred at room temperature for 1 hour and then 150 ml of water was added. We separated the phase. The aqueous phase was extracted with 1,2-dichloroethane and the extracts were added to the organic phase, which was then washed with cold saturated sodium bicarbonate solution, washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 10.7 g of the title compound, m.p. Mp 152-155 ° C.

8- (N-acetyl-N- (2-chloroethyl) -aminomethyl1-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXIII)

8.65 g of intermediate XXX and 4.15 ml of triethylamine were dissolved in 70 ml of tetrahydrofuran. A solution of 2.35 ml of acetyl chloride in 23 ml of tetrahydrofuran was added dropwise over 40 minutes to this solution at -10 ° C. After stirring for 3 hours at 0 to 10 ° C and 2 hours at 20 to 25 ° C, the solvent was evaporated in vacuo. To the residue was added 100 ml of water and extracted with dichloromethane, the successive organic extracts were combined together and the solvent was removed in vacuo. The residue was dissolved in 50 ml of methanol and 3 g of potassium carbonate and 10 ml of water were added. After stirring at 50 ° C for 20 minutes to hydrolyze the resulting Ν, di-diacetyl derivative, the solvent was removed in vacuo and the residue was treated with water and dichloromethane as described above. The dichloromethane solution was re-evaporated to dryness to give 5.9 g of 8- [N-acetyl-N- (2-hydroxyethyl) -aminomethyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, m.p. 171-172 ° C. To a solution of 6.1 g of the compound thus prepared in 70 ml of dichloromethane was added dropwise at 0 ° C 3.6 ml of thionyl chloride in 30 ml of dichloromethane. After stirring at 20 to 25 ° C for 90 minutes, the reaction mixture was washed with water and dried. The solvent was removed in vacuo to give the crude title product for use without further purification.

8- (3-chloropropylthio) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXIV)

A solution of 20.1 g of tin (II) hydrochloride dihydrate in 18 ml of hydrochloric acid (d = 1.18) was added over a period of 5 minutes at 65 ° C to a solution of 6 g of intermediate VIII in 70 ml of acetic acid. After 10 minutes, the reaction mixture was cooled to 30-35 ° C and the solvent was removed in vacuo. The residue was taken up in water, the insoluble matter was collected by suction filtration, washed with water and dried. Yield: 3.2 g of 8-mercapto-3-methyl4-oxo-2-phenyl-4H-1-benzopyran, which melts after crystallization from ethanol at 115 to 118 ° C.

A mixture of 8 g of the compound thus prepared, 27 ml of 1-bromo-3-chloro-propane, 0.2 g of tetrabutylammonium bromide and 6.2 ml of 35% sodium hydroxide in 80 ml of benzene was stirred vigorously for 4 hours at 20 to 25 °. C. 100 ml of water and 40 ml of dichloromethane were added. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvents and excess of 1-bromo-3-chloro-propane were removed in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 9: 1 to give 5.7 g of the title compound. After crystallization from methanol, the melting point was 84 to 86 ° C.

8- (3-chloropropylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

XXXV) ml of 30% hydrogen peroxide was added at 20 to 25 ° C to a solution of 3.45 g of intermediate XXXIV in 35 ml of acetic acid. After stirring for 4 hours at 60 ° C, the reaction mixture was cooled to 20 to 25 ° C. 30 ml of water were added. A precipitate formed which was collected by suction filtration, washed with water and dried to give 3.4 g of the title compound. After crystallization from acetone, the melting point was 160 to 163 ° C.

8- (3-hydroxypropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

XXXVI)

A solution of 7.6 ml of 3-aminopropanol in 50 ml of water was added dropwise 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 dropwise over 30 minutes. g of potassium carbonate in 400 ml of acetone. The thick suspension was stirred for 3 hours at up to 25 ° C. The solvents were removed in vacuo and the residue was taken up in 300 ml of water. After stirring for 1 hour, the precipitate was collected by suction filtration and washed with water. The crude product was purified by crystallization from 95% ethanol to give 23.8 g of the title compound, m.p. 191 to 193 ° C. Concentration of the crystallization filtrate in vacuo gave an additional 4.7 g of the title compound.

8- (3-chloropropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXVII)

A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was added to a boiling solution of 3.37 g of intermediate XXXVI in 20 ml of chloroform. After 90 minutes of stirring under reflux, the solvent was removed in vacuo and the residue was crystallized from acetonitrile to give 3 g of the pure title compound, m.p. (188) 193-194 ° C.

8-fluoro-4- (4-methylphenylsulfonyloxy) -butyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran (Intermediate XXXVIII)

1.12 g of sodium cyanide in 3 ml of water was added at 20-25 ° C while stirring to a mixture of 3.96 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 2. 61 g of morpholine and 4.48 g of p-toluenesulfonic acid in 20 ml of tetrahydrofuran and 30 ml of 1,2-dichloroethane. The reaction mixture was refluxed for 4 hours and then 10 ml of cold water was added. The tetrahydrofuran was distilled off under normal pressure and 10 ml of 1,2-dichloromethane and 10 ml of chloroform were added. The organic phase was separated, washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was suspended in diethyl ether, filtered off and crystallized from chloroform: ethyl acetate. Yield: 3.55 g of 8- (morpholino-cyanomethyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran, m.p. 236-238 ° C.

3.5 ml of 30% potassium hydroxide solution in anhydrous methanol were added while stirring at room temperature 22.8 g of the compound thus prepared in 520 ml of anhydrous tetrahydrofuran was added to the suspension. To this suspension was added 6.3 ml of acrylonitrile in 20 ml of tetrahydrofuran and the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated in vacuo. Crystallization of the methanol residue gave 23.22 g of 8- (1,3-dicyano-1-morpholino-propyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 23.2 g of the compound thus prepared were dissolved in 250 ml of dioxane. 250 ml of 6M hydrochloric acid were added and the mixture was refluxed for 2½ hours. After cooling to room temperature, the mixture was poured into 700 ml of aqueous sodium chloride solution and extracted with ethyl acetate. The extracts were washed with aqueous sodium chloride solution and treated with 700 ml of IM sodium hydroxide solution. The aqueous layer was washed with ethyl acetate and acidified with 37% hydrochloric acid. The precipitate was collected by suction filtration and crystallized from ethanol to give 10.2 g of 8- (3-carboxy-1-oxopropyl) -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, m.p. 191-192 ° C.

Diborane, which was developed by instillation of a solution of 2.1 ml of freshly distilled boron trifluoride diethyl etherate in 10 ml of anhydrous diglyme in 19 ml of 0.66 M sodium borohydride solution in diglyme, was bubbled through a suspension of 2.28 g of the compound thus prepared in 23 ml of anhydrous tetrahydrofuran stirred at 0 ° C under a stream of nitrogen. Stirring was continued for 20 minutes at 0 ° C and another 20 minutes at room temperature. Methanol was carefully added to the mixture at 0 ° C to terminate the reaction. The solvents were removed by evaporation in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether: ethyl acetate 3: 7. The collected fractions were evaporated in vacuo to give 2 g of 8- (1,4-dihydroxybutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 133-134 ° C.

While stirring, 2.8 g of p-toluenesulfonyl chloride was added to a solution of 3.17 g of the compound thus prepared in 32 ml of anhydrous pyridine at 0 ° C. The mixture was stirred for 6 hours at 0 ° C and allowed to stand at -4 ° C overnight without stirring. It was then poured into 200 ml of aqueous sodium chloride solution, acidified with 10 ml of 12M hydrochloric acid and filtered by suction. The filter cake was dissolved in chloroform and the solution was washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off on a rotary evaporator. The residue was purified by flash chromatography on silica gel eluting with petroleum ether: ethyl acetate 1: 1. The collected fractions were evaporated to dryness to give 3.04 g of pure title compound, m.p. 123-124 ° C.

4- [4- (2-Methoxyphenyl) -1-piperazinyl-butyraldehyde (Intermediate XXXIX)

A solution of 5.4 g of 2- (3-chloropropyl) -dioxolane and 15.9 g of 1- (2-methoxyphenyl) -piperazine in 60 ml of dimethylformamide was stirred at 80 ° C for 4 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 500 ml of ice-cold 0.5 N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluting with dichloromethane: ethanol 95: 5. 9.8 g of 2- {3- [4- (2-methoxyphenyl) -1piperazinyl] -propyl} -dioxolane was obtained as an oil.

NMR CDC1 ₃ (δ)

1.5-2.0 (4H, m, CH ₂ CH ₂ CH)

2.2- 3.2 (10Η, m, 5xCH ₂ N)

3.7- 4.0 (7H, m, OCH ₃ and 2 x OCH ₂ )

4.8 (1H, t, OCHO)

6.7- 6.9 (4H, m, aromatic protons)

A solution of 12.8 g of the compound thus prepared in 200 ml of tetrahydrofuran and 420 ml of 1N hydrochloric acid was maintained at 20 to 25 ° C for 24 hours. It was then basified with 5N sodium hydroxide solution and immediately extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane: methanol 97: 3. 6.4 g of the title compound were obtained as an oil.

NMR CDC1 ₃ (S)

1.5-2.0 (2H, m, CH ₂ CH ₂ CH ₂ )

2.2-2.8 (8H, m, 3 x CH ₂ N and CH ₂ CHO)

2.9-3.2 (4H, m, 2xCH ₂ NAr)

3.8 (3H, s, OCH ₃ )

6.8 (4H, s, aromatic protons)

9.3 (1H, s, CHO).

8- (2 _< 3-epoxypropoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XL) ml of 2,3-epoxypropyl chloride was added dropwise at 20 to 25 ° C while stirring to a solution of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 ml of 2N sodium hydroxide in 10 ml of ethanol. After 6 hours at 20 to 25 ° C, the reaction mixture was poured into 100 ml of water and the resulting precipitate was collected by suction filtration. After drying and purification by flash chromatography on silica gel (eluent: petroleum ether: ethyl acetate 65:35), 4.45 g of the title compound are obtained, m.p. 128-129 ° C.

8- [N-methyl-2- (4-methylphenylsulfonyloxy) -ethylsulfamoyl] -3-methyl-4-oxo-2-phenyl4H-1-benzopyran (Intermediate XLI)

A solution of 5 g of intermediate VIII in 60 ml of dichloromethane and 20 ml of tetrahydrofuran was added dropwise at 0 ° C to a mixture of 2.5 ml of 2-methylaminoethanol and 2.1 ml of triethylamine in 20 ml of dichloromethane. After stirring at 20 to 25 ° C for 2 hours, 100 ml of water and 100 ml of dichloromethane were added to the reaction mixture. The phases were separated and the organic solution was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 3: 7. 4.5 g of 8- (N-methyl-2-hydroxyethylsulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran were obtained, which, after crystallization from ethanol, melted at 146 to 147 ° C.

The compound thus prepared was converted to the title compound by p-toluenesulfonylation according to the second step of the procedure described below for the preparation of intermediate XLII. The title compound was used without further purification.

8- (2- (4-methylphenylsulfonyloxy) -ethylsulfamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLII)

A solution of 5 g of intermediate VIII in 37 ml of tetrahydrofuran was added dropwise at 0 ° C to a mixture of 2.5 ml ethanolamine and 2.5 ml triethylamine in 25 ml tetrahydrofuran. After stirring at 20 to 25 ° C, the reaction mixture was poured into 400 ml of water. A precipitate formed which was collected by suction filtration, washed with water and air-dried to give

4.6 g of 8- (2-hydroxyethylsulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran which, after crystallization from ethyl acetate, melts at 186 to 187 ° C.

To a solution of 3.6 g of the compound thus prepared in 25 ml of pyridine was added at 0 ° C in portions 2.1 g of p-toluenesulfonyl chloride. After 6 hours at 20 to 25 ° C, the reaction mixture was slowly poured onto crushed ice containing a small excess of hydrochloric acid. A precipitate formed which was collected by suction filtration and washed with water. 4.9 g of the title compound are obtained, which melts after crystallization from ethyl acetate at (163) 166-169 ° C.

8- (3-Aminopropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride (Intermediate XLIII)

A solution of 21.6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 250 ml of anhydrous tetrahydrofuran was added dropwise at 0 to 10 ° C while stirring in a solution of 17 g of 3- (2 -methyl-2-propoxycarbamoyl) propylamine (prepared as described in Saari, WS et al., J. Med. Chem. 33, 97,1990) and 13 ml of triethylamine. After stirring at room temperature for 2 hours, the reaction mixture was poured into water and filtered to give 12.3 g of 3- (2-methyl-2-propoxycarbamoyl) -propyl-3-methyl-4-oxo-2-phenyl4H-1 -benzopyran-8-carboxamide, which was recrystallized from ethanol. Tal. 178-180 ° C.

While stirring at -5 ° C, a solution of 4.3 ml of trifluoroacetic acid in ml of anhydrous dichloromethane was added dropwise to a solution of 3.3 g of the compound thus prepared in 35 ml of anhydrous dichloromethane. After warming to room temperature, the mixture was stirred for 8 hours. Dichloromethane and excess trifluoroacetic acid were evaporated at 20 to 25 ° C using a rotary evaporator. The oily residue was dissolved in dichloromethane and a 1N sodium hydroxide solution was added. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. Excess ethanol hydrogen chloride was added to the filtrate and the solvent was removed in vacuo. The residue was crystallized from ethanol to give 1.5 g of the title compound, m.p. 253 to 255 ° C.

8- (2-Chloroethylureido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLIV)

To a solution of 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 52 ml of anhydrous dimethylformamide was added 4 ml of 2-chloroethyl isocyanate while stirring at room temperature. Stirring was continued at 70 ° C for 5 hours. Water was added to the reaction mixture and then extracted with ethyl acetate. The organic phase was evaporated to dryness in vacuo. The residue was suspended while stirring in diethyl ether. The title compound was then filtered off and recrystallized from methanol. Yield: 3.74 g, m.p. 213 to 214 ° C.

(Z, E) -8- {4- [2- (1,3-dioxanyl)] -1-butenyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLV)

1.6 ml of 2.5N butyllithium in hexane was added dropwise at -20 ° C to a solution of 1.53 g of 2- (2- (1,3-dioxanyl)] - ethyl-triphenylphosphonium bromide in 10 ml of anhydrous tetrahydrofuran. was stirred for 20 minutes at -20 [deg.] C. A solution of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 11 ml of anhydrous tetrahydrofuran was added dropwise to the mixture and the mixture was then warmed to The reaction was quenched by the addition of methanol, the solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3: 7 to give the title compound as a mixture of diastereoisomers E and Z, mp (93) 98-100 [deg.] C. The ratio of the two isomers was determined by NMR spectroscopy and was E: Z = 65:35.

NMR, CDCl ₃ (S)

8.1-8.2 (m, 1H, CH in position 5 of the benzopyran ring)

7.2-7.8 (m, 7H, other aromatic CH groups of benzopyran and phenyl rings)

6.9 (dt, 1H, F1′-CH E-isomer)

6.8 (dt, 1H, Ff-CH Z-isomer)

6.4 (dt, 1H, F1′-CH = CH E-isomer)

5.9 (dt, 1H, F1′-CH = CH Z-isomer)

4.6- 4.7 (m, 1H, OCHO)

3.6-4.2 (m, 4H, OCH ₂ O dioxane ring)

2.4-2.7 (m, 2H, CHCH ₂ CH)

1.9-2.3 (m, 5H, CH ₃ and CH ₂ in position 5 of the dioxane ring)

8- {4-2- (1,3-dioxanyl)] -butyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLVI)

A mixture of 0.2 g of catalyst a, 10% palladium on charcoal and 1 g of intermediate XLV in 24 ml of methanol was hydrogenated in a Parr apparatus at room temperature with a hydrogen pressure of 1.47 bar. After theoretical consumption of hydrogen, the catalyst was filtered off and the solvent was removed by evaporation in vacuo. The residue was crystallized from cyclohexane to give the title compound, m.p. 118 to 119.5 ° C.

8-Carboxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLVII)

4.5 g of potassium permanganate were added in portions over 1½ hours while stirring at 0 to 10 ° C to a mixture of 2.76 g of 8-allyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (P. Da Re, US 3,350,411), 0.17 g Aliquat 336,1.12 ml acetic acid, 56 ml dichloromethane, 3.2 ml sulfuric acid (d = l, 84) and 60 ml water. Stirring was continued at room temperature for 5 hours. 3.4 g of sodium metabisulphite were added after 15 minutes at portions at 0 to 5 ° C. The organic layer was separated, washed with water and extracted with 60 ml of 1N aqueous sodium hydroxide solution. The aqueous phase was acidified by the addition of dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness after filtration. The residue was treated with carbon tetrachloride and the solid was collected by suction filtration to give 1 g of the title compound, m.p. 191 to 192 ° C (acetonitrile).

8- (4-chlorobutyramido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLVIII)

The title compound was prepared in the same manner as intermediate X except that 4-chlorobutyryl chloride was used instead of acryloyl chloride. The resulting solid, which was filtered from water and dried, was washed with hot diethyl ether and collected by suction to give the title compound. The sample, which was crystallized from 50% aqueous ethanol and washed with diethyl ether, was melted at (153) 162-164 ° C.

8-Methylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLIX)

A solution of 0.5 g of intermediate XXIII in 1.5 ml of anhydrous dimethylformamide was added dropwise, while stirring at -5 ° C, to a suspension of 0.045 g of sodium hydride (80% in mineral oil). After stirring at room temperature for 1 hour, 0.092 ml of methyl iodide and 0.6 ml of anhydrous dimethylformamide were added dropwise. The reaction mixture was then stirred at 50 ° C for 1 hour, cooled to 20 ° C, poured into water, filtered by suction and dried for 3 hours at 60 ° C to give 0.6 g of 8- (Nmethyltrifluoroacetamido) -3-methyl -4-Oxo-2-phenyl-4H-1-benzopyran.

NMR (CDC1 ₃ , (δ)

8.15 (dd, 1H, benzopyran CH in 5)

7.10-7.60 (m, 7H, other benzopyran and phenyl CH)

3.30 (s, 3H, CH ₃ -N)

2.10 (s, 3H, benzopyran CH ₃ in 3)

A mixture of 0.44 g of the above compound and 0.05 g of sodium borohydride in 4 ml of ethanol and 1 ml of dimethylsulfoxide was stirred at room temperature for 1 hour and then poured with excess 4N hydrochloric acid. After removal of the ethanol by evaporation in vacuo, the residue was washed with water, then with 3N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The solid residue was crystallized from ethanol to give 0.22 g of the title compound, which melted at 143 to 146 ° C.

8- (N-methylacrylamido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate L)

This compound was prepared in the same manner as intermediate X except that intermediate XLIX was used instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Instead of diluting with water, THF was removed by evaporation in vacuo and the crude residue was dissolved in ethyl acetate and washed with water. The organic solution was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give the title compound. The sample, which was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether 4: 6) and crystallized from cyclohexane, melted at 136-137 ° C.

1- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yloxy) -ethyl] -4- (2-methoxyphenyl) -piperazine (Intermediate LI)

A mixture of 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium acetate and 10 g of 1- (2-chloroethyl) -4 (2-methoxyphenyl) piperazine in 100 ml of anhydrous dimethyl sulfoxide was stirred at 100 ° C for 4 hours. The reaction mixture was then cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo to give 7.58 g of the title compound. The sample was crystallized from cyclohexane and found to melt at (76) 80 to 83 ° C.

1- (2-aminooxyethyl) -4- (2-methoxyphenyl) -piperazine hydrochloride (Intermediate Lil)

A solution of 6.59 g of intermediate LI and 1.10 ml of 85% hydrazine hydrate in 130 ml of 95% ethanol was refluxed for 4 hours. The ethanol was removed by evaporation in vacuo. The residue was rinsed with water and then excess 37% hydrochloric acid was added and filtered. The acidic aqueous solution was basified with 5% sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 4.3 g of the title compound as an oil. The sample was converted to the hydrochloride by converting it to a salt with ethanol hydrochloride in dichloromethane. The solvents were removed by evaporation in vacuo and the crude residue was crystallized from ethanol to give the title compound, m.p. Mp 208-209 ° C.

8- (4-chlorobutylthio) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LIH)

The title compound was prepared in the same manner as intermediate XXXIV except that 1-bromo-4-chlorobutane was used instead of 1-bromo-3-chloropropane. Tal. 81-84 ° C (ethanol).

8- (4-Chlorobutylsulfinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LIV)

The title compound was prepared in the same manner as intermediate XXVI, except that intermediate LIH was used instead of intermediate XXI. A sample recrystallized from cyclohexane: benzene 0.5: 1 was melted at 124-125 ° C.

8-Carboxy-4-oxo-3-phenyl-4H-1-benzopyran (Intermediate LV)

A solution of 38.22 g of silver nitrate in 75 ml of water was added dropwise at 20 to 25 ° C to a solution of 22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared as describe G. Atassi et al., Eur. J. Med. Chem. - Chim. Ter., 20, 393 (1985)) in 150 ml of 85% ethanol and 450 ml of dimethylformamide. A solution of 32.67 g of 85% potassium hydroxide in 195 ml of water was then added dropwise while stirring at 15 to 20 ° C. After further stirring at room temperature, the reaction mixture was filtered by suction; The mother liquor was acidified with 37% hydrochloric acid and diluted with 1.2 liters of water. Filtration by suction and washing with water to neutrality gave the title compound as a crude product. This was suspended in 150 ml of ethyl acetate and stirred with 444 ml of 0.3 M sodium hydrogen carbonate until clear layers were obtained. The aqueous layer was washed with 75 ml of ethyl acetate, then acidified with 37% hydrochloric acid, filtered and dried at 60 to 65 ° C to give 19.12 g of the title compound, which melted at (215) 218 ° C. The sample crystallized from ethanol had the same melting point.

8-Chlorocarbonyl-4-oxo-3-phenyl-4H-1-benzopyran (Intermediate LVI)

A mixture of 15.97 g of LV intermediate and 15.6 ml of thionyl chloride in 75 ml of anhydrous toluene was stirred at 80 to 85 ° C for 4 hours. After removal of the solvent in vacuo, the residue was rinsed twice with 20 ml of toluene and evaporated to dryness in vacuo to give, after drying, 16 g of the title compound, which melted at (126) 138-140 ° C, which was used without additional cleaning. Tal. (130) 138-140 ° C (toluene).

8- [N-acetylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LVII)

A mixture of 3.5 g of 8-carbamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (described in JP 61-238783), 4.8 ml of acetic anhydride and 0.25 ml of sulfuric acid ( d = 1.098) was stirred at 140 ° C for 3 minutes. The reaction mixture was cooled to room temperature, diluted with water and filtered by suction to give 3.88 g of the title compound after washing with water and drying.

NMR (CDCl ₃ , δ)

10.50 (bs, 1H, Imid NH)

8,35-8,70 (m, 2H, CH in positions 5 and 7 of the benzopyran ring)

7.45-8.00 (m, 6H, other aromatic CH ₃ )

2.60 (s, 3H, CH ₃ CO)

2.20 (s, 3H, CH ₃ at position 3 of the benzopyran ring)

2- (2-methylthiophenoxy) -acetaldehyde diethyl acetal (Intermediate LVIII)

A mixture of 15.2 ml of 97% bromoacetaldehyde diethyl acetal, 14 g of 2- (methylthio) phenol, 13.7 g of anhydrous potassium carbonate and 3.13 g of tricaprylmethylammonium chloride in 140 ml of anhydrous dimethylformamide was stirred at 95 ° C for 38 hours . After this time, the reaction mixture was cooled to room temperature, poured into 1 liter of water and extracted with diethyl ether. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The oily residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 99: 1. Evaporation of the collected fractions in vacuo gave 12.9 g of the pure title compound. The sample crystallized from n-hexane melted at 50-52 ° C.

2- (2-methylthiophenoxy) -acetaldehyde (Intermediate LIX)

A mixture of 10.5 g of LVIII intermediate and 140 ml of 2N hydrochloric acid in 85 ml of anhydrous tetrahydrofuran was stirred at 50 ° C for 2 hours. The organic solvent was then removed by evaporation in vacuo and the aqueous residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give 9.5 g of the title compound as a solid, which was used without further purification. The sample crystallized from cyclohexane gave the pure title compound from the ground. 102 to 104 ° C.

8- (4-Chlorobutylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LX)

The title compound was prepared by the same method as intermediate XXV except that LIH was used instead of intermediate XXI. It was crystallized from diisopropyl ether and melted at 112 to 115 ° C.

8-Ethoxycarbonyl-4-oxo-4H-1-benzopyran (Intermediate LXI)

4.35 g of metallic sodium in pieces was added at room temperature to a solution of 9.85 g of ethyl 3-acetyl-2-hydroxy benzoate (synthesized from 3-acetyl-2-hydroxybenzoic acid (prepared as described by RE Ford, J. Med. Chem., 29, 538 (1986), refluxed

On ethanol hydrogen chloride for 1.5 hours, evaporated to dryness in vacuo and the crude product was purified by silica gel column chromatography (eluent ethyl acetate - petroleum ether 8: 2) - mp. 47 ° C (hexane)) in 98 ml of ethyl formate.

The reaction mixture refluxed for 20 minutes by itself. It was then stirred at room temperature for 4 hours and the ethyl formate was removed by evaporation to dryness in vacuo. The crude solid obtained was rinsed with 120 ml of ethanol and 67 ml of 5.6 M ethanol hydrochloride. The mixture was stirred at reflux for 30 minutes. It was then cooled to room temperature and evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 3: 7 to 6: 4 to give 8.31 g of the title compound. The sample, which was crystallized from cyclohexane, was melting at 88 to 89 ° C.

8-Carboxy-4-oxo-4H-1-benzopyran (Intermediate LXII) ml of 6 N hydrochloric acid was added to a solution of 4.0 g of intermediate LXI in 30 ml of dioxane and the resulting mixture was stirred at reflux for 5 hours. The reaction mixture was cooled to room temperature and poured into 200 ml of water. After 12 hours at 0 to 5 ° C, the title compound was filtered off by suction. Washing with water and diethyl ether afforded 2.8 g of the title compound after drying, which was used without further purification. The sample, which was washed with boiling acetonitrile: methanol 25: 1, filtered and crystallized from acetic acid, was melted at 253-254 ° C.

8-Carboxy-6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXIII)

A mixture of 1.5 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in JP 61-15880) and 28 ml of 57% hydrogen iodide of acid in 47 ml of acetic acid was stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and poured into water. 1N sodium hydroxide was added to adjust the pH to 4 to 5. 2 g of sodium thiosulphate was added and stirring was continued for 15 minutes. After this time, the crude title compound was filtered off by suction and dissolved in 0.5 N sodium hydroxide. The basic solution was washed with ethyl acetate and acidified to pH 1 with the addition of 37% hydrochloric acid. The title compound was collected by suction and dried. Yield: 1.12 g of the title compound which was used without further purification and which, after crystallization from 50% ethanol, melted at 279 to 281 ° C.

2-Hydroxy-5-nitro-3-propionyl-benzoic acid (Intermediate LXIV)

97.1 g of 2-hydroxy-3-propionyl-benzoic acid, as described in Brit 1,343,119 (1974), was added over 5 minutes to 500 ml of sulfuric acid (d = 1.84), which was stirred at - 25 ° C. A mixture of 40 ml of 65% hydrochloric acid and 100 ml of sulfuric acid (d = 1.84) was added over a period of 40 minutes, maintaining the temperature of the reaction mixture between -20 and -13 ° C. The mixture was stirred at -18 ° C for another 30 minutes. After this time, it was carefully poured into a mixture of 2.0 kg of crushed ice and 500 ml of water, stirred for 10 minutes and filtered to give the title compound after washing with water and drying at 50 ° C for 6 minutes. Crystallization of this solid from 50% ethanol gave 91.5 g of the title compound, which melted at 186 to 189 ° C and was used without further purification. The sample recrystallized from 50% ethanol melted at 189 to 191 ° C.

Ethyl 2-hydroxy-5-nitro-3-propionyl-benzoate (Intermediate LXV)

A solution of 93.3 g of LXIV intermediate and 25 ml of sulfuric acid (d = 1.84) in 490 ml of ethanol was refluxed for 17 hours. After cooling to room temperature, 47.7 g of sodium carbonate was added in portions and the ethanol was evaporated in vacuo. The residue was washed with 1.2 l of water, basified with the addition of 37% sodium hydroxide and stirred for 15 minutes. 37% hydrochloric acid was added to this suspension to adjust the pH to 6. Filtration gave 85.4 g of the title compound, which was used without further purification (mp 75-77 ° C). The sample, which was crystallized twice from ethanol, melted at 76-77 ° C.

8-Ethoxycarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

LXVI)

A mixture of 48.1 g of LXV intermediate, 63 ml of benzoyl chloride and 85.6 g of sodium benzoate was stirred at 180 ° C (bath temperature) for 8 hours. The paste mixture was cooled to 60-70 ° C. 700 ml of 50% ethanol were added and the resulting mixture was stirred again at 50 ° C for 30 minutes. At 5 ° C, 60 ml of 35% sodium hydroxide was added while maintaining that the temperature did not rise above 15 ° C. The suction filtration, followed by washing with 50% ethanol and water, gave a crude product which was purified by passing it 2 times through a silica gel chromatography column, eluting first with dichloromethane: petroleum ether gradient 8: 2 to 9: 1, then dichloromethane and finally dichloromethane: ethyl acetate 95: 5. Evaporation of the collected fractions in vacuo gave the title compound, which was washed with 140 ml of ethanol. Yield: 43 g, m.p. 132-133 ° C (ethanol).

8-Carboxy-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXVII)

A mixture of 15.9 g of LXVI intermediate and 48 ml of IN sodium hydroxide in 320 ml of ethanol was stirred at reflux for 30 minutes. The organic solvent was removed by evaporation in vacuo and the resulting suspension was diluted with 200 ml of water and acidified with 37% hydrochloric acid. Filtration and washing with diethyl ether gave 1.1 g of the title compound, which melted at (258) 286-292 ° C and was used without further purification. After crystallization from dimethylformamide: water 6: 4, the title compound showed the same melting point.

8-Chlorocarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXVIII)

A mixture of 6.2 g of intermediate LXVII, 5.2 ml of thionyl chloride and 0.1 ml of anhydrous dimethylformamide in 60 ml of toluene was stirred at 90 ° C for 2 hours. Evaporation to dryness in vacuo and drying gave 6.5 g of the title compound, m.p. 161-162 ° C, which was used without further purification. The sample crystallized from toluene had the same melting point.

8-Carboxy-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXIX)

216 ml of 0.3 M potassium permanganate solution in water were added dropwise over 40 minutes to a mixture of 7.94 g of 8-formyl-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-benzopyran (prepared , as described by Da Re et al., J. Org. Chem., 25, 1097, 1960) and 54 ml of 5% sodium dihydrogen phosphate in 162 ml of t-butanol, which was stirred at 75 ° C. After stirring for a further 2½ hours at the same temperature, the reaction mixture was cooled to room temperature and 81 ml of IM sodium dithionite was slowly added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed 4 times with 160 ml of 0.5 N sodium hydroxide. The collected basic aqueous layers were washed with diethyl ether and acidified with 37% hydrochloric acid. The title compound precipitated. It was filtered off and washed with water to give 3.3 g after drying, which were used for further reactions without further purification and which, after crystallization from 95% ethanol, melted at 180 to 181 ° C.

Ethyl 3-propionyl-2- (4-trifluoromethylbenzoyloxy) -benzoate (Intermediate LXX)

A solution of 6.7 g of 4-trifluoromethylbenzoyl chloride (prepared from the corresponding benzoic acid and thionyl chloride in benzene at reflux and used without purification) in a solution of 7.13 g of ethyl 2-hydroxy-3-propionylbenzoate and 4 was added dropwise. , 9 ml of triethylamine in 50 ml of chloroform. The mixture was stirred at room temperature for 2 hours. The solvent was then evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 85:15. Influence of the collected fractions in vacuo to dryness afforded 7.4 g of the title compound as an oil.

NMR Spectrum at 60 MHz (CDC1 ₃ , δ)

7.6-8.5 (m, 6H, aromatic CHs)

7.5 (t, 1H, phenolic ring, CH in 5)

4.2 (q, 2H, COOCH ₂ )

2.9 (q, 2H, COCH ₂ )

1-1,3 (2t, 6H, 2xCH ₃ )

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyran (Intermediate LXXI)

A mixture of 6.96 g of LXX intermediate and 2.58 g of potassium t-butoxide in 35 ml of pyridine was stirred at 100 ° C for 2 hours. After this time, the reaction mixture was cooled to room temperature, poured into a solution of 50 ml of acetic acid in 600 ml of water and extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 6.9 g of 1- (2-hydroxy-3-ethoxycarbonyl) -2-methyl- 3- (4-Trifluoromethylphenyl) -1,3-propanedione. A solution of the compound thus prepared and 2.2 ml of 37% hydrochloric acid in 35 ml of glacial acetic acid was stirred at 100 ° C for 1½ hours. After cooling to room temperature, the mixture was poured into 630 ml of 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The crude material was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 85:15. Evaporation to dryness afforded 2.95 g of the title compound which, after crystallization from cyclohexane, melted at 111 to 113 ° C.

8-Carboxy-3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyran (Intermediate LXXII)

A mixture of 2.95 g of intermediate LXXI and 0.43 g of lithium hydroxide monohydrate in 12.5 ml of methanol and 12.5 ml of tetrahydrofuran containing 8 ml of water was stirred at room temperature for 1½ hours. The mixture was poured into a solution of 30 ml of 1N hydrochloric acid in 300 ml of water and filtered by suction to give 2.47 g of the title compound, which was used without further purification. The sample, which was crystallized from 60% ethanol, was melted at 253 to 254 ° C.

8-Ethoxycarbonyl-2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXIII)

The title compound was synthesized by the process for intermediate LXX and LXXI in the order indicated, except that it was derived from 4-benzoylbenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride, and that the compound was metabolised in 1,2-dichloroethane instead of chloroform and in the presence of 4-dimethylaminopyrid instead of triethylamine. After usual processing, the residue was purified by silica gel column chromatography eluting with dichloromethane: ethyl acetate 9: 1. Influence of the collected fractions in vacuo to dryness gave the title compound, which was used without further purification. The sample, which was crystallized from cyclohexane, melted at 125-136 ° C (dec.).

8-Carboxy-2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXIV)

The title compound was prepared in the same manner as intermediate LXXII except that it was derived from intermediate LXXIII instead of intermediate LXXI. It was purified by dissolving the crude material in 0.5M sodium hydroxide, washing the aqueous layer with ethyl acetate and precipitating the pure title compound with the addition of 37% hydrochloric acid. The sample, which was crystallized from acetic acid, was melting at 260 to 262 ° C.

Ethyl 2- (4-phenoxybenzoyloxy) -3-propionyl-benzoate (Intermediate LXXV)

The title compound was prepared according to the procedure described for intermediate LXX, except from 4-phenoxybenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride. Solvent evaporation gave the pure title compound.

NMR Spectrum at 200 MHz (CDC1 ₃ , S)

8.17 (dd, 3H, phenyl CHs in the ortho position with respect to the carboxylate groups)

7.92 (dd, 1H, phenyl CH in the ortho position with respect to the CO group)

7.38-7.48 (m, 3H, phenyl CHs in meth position with respect to carboxylate groups)

7.25 (d, 1H, CH in position 4 of the phenoxy ring)

7.05; 7.10 (2d, 4H, other CH phenoxy ring)

4.25 (q, 2H, CH ₂ O)

2.90 (q, 2H, CH ₂ CO)

1.05 to 1.20 (m, 6H, 2xCH ₃₎

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran (Intermediate LXXVI)

The title compound was prepared in the same manner as intermediate LXXI except that it was derived from intermediate LXXV instead of intermediate LXX. It was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 6: 4. Evaporation in vacuo gave the pure title compound, m.p. 98 to 100 ° C.

8-Carboxy-3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran (Intermediate

LXXVin

This compound was obtained in the same manner as intermediate LXXII except that it was derived from intermediate LXXVI instead of intermediate LXXI. Tal. 216 to 218 ° C.

8-Carboxy-2- (t-butyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXVIII) ml pivaloyl chloride was added dropwise while stirring to a solution of 8.9 g of ethyl

Of 2-hydroxy-3-propionyl-benzoate in 20 ml of anhydrous pyridine. The reaction mixture was stirred at 80 ° C for 6 hours, cooled to room temperature and poured into a mixture of 200 g of crushed ice and 30 ml of 10 N hydrochloric acid. After extraction with diethyl ether, the organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 11.4 g of crude ethyl 2-pivaloyloxy-3-propionylbenzoate.

2.4 g of this compound was dissolved in 4 ml of anhydrous pyridine and 1 g of anhydrous potassium t-butoxide was added. The resulting mixture was heated at 100 ° C for 15 minutes, cooled to room temperature, and poured into 50 g of ice-water containing 8 ml of 10 N was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 2.1 g of crude ethyl 2-hydroxy-3- (2-pivaloylpropionyl) -benzoate, which was used without purification in the next step. 2 g of the compound thus prepared was heated at 100 ° C for 15 minutes after being dissolved in a mixture containing 15 ml of acetic acid and 1.5 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 100 ml of water and extracted with diethyl ether. The organic phase was washed with 5% aqueous sodium hydrogen carbonate and then with water, dried on anhydrous sodium sulfate and evaporated in vacuo to give 1.6 g of crude 8-ethoxycarbonyl-2- (t-butyl) -3- methyl-4-oxo-4H-1-benzopyran.

1.5 g of the above ester was dissolved in 20 ml of methanol. 3 ml of 10 N sodium hydroxide was slowly added while maintaining the temperature between 25 and 35 ° C. After 1 h at room temperature, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The aqueous layer was acidified with 3 N hydrochloric acid. The precipitate was collected by suction, washed with water and crystallized from ethanol to give 0.8 g of the title compound, which melted at 225 to 228 ° C.

8-Carboxy-2-cyclohexyl-3-methyl-4-oxo-4H-benzopyran (Intermediate LXXIX)

This compound was prepared according to the reaction sequence and methods described for intermediate LXXVIII, except that it was derived from cyclohexylcarboxylic acid instead of pivaloyl chloride and with other minor differences. Specifically, ethyl 2-cyclohexylcarbonyloxy-3-propionyl-benzoate was obtained after stirring for 8 hours at pyridine at room temperature and converted to ethyl 2-hydroxy-3- (2cyclohexylcarbonyl-propionyl) -benzoate after 2½ hours of heating with potassium t-butoxide at 100 ° C. Cyclization to 8-ethoxycarbonyl-2-cyclohexyl-3-methyl-4-oxo4H-1-benzopyran was carried out by heating for 1½ hours in a mixture of acetic acid and hydrochloric acid at 100 ° C and hydrolysis of the title compound was carried out in 20 minutes at room temperature. The title compound was melted after crystallization from 40% ethanol at 224 ° C.

8-Ethoxycarbonyl-2- (2-furyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXX)

A mixture of 3.2 g and XC intermediate and 1.3 g of anhydrous potassium t-butoxide in 8 ml of anhydrous pyridine was stirred at 60 ° C for 15 minutes, cooled to room temperature and poured into 60 ml of ice water containing 15 ml 10 N hydrochloric acid. After extraction with ethyl acetate, the organic phase was washed with 5% aqueous sodium bicarbonate and water and dried over anhydrous sodium sulfate. After evaporation in vacuo, 2.5 g of crude 3- (2-furoyl-propionyl) -2-hydroxy-benzoate were obtained.

2.5 g of the compound thus obtained were stirred at 100 ° C for 30 minutes with 10 ml of acetic acid and 0.7 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 180 ml of water. The title compound precipitated, which was collected by suction filtration, washed with water and crystallized from isopropanol. Yield: 1.5 g, m.p. 137 to 139 ° C.

8-Carboxy-2- (2-furyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXI)

A mixture of 3.5 g of LXXX intermediate and 6 ml of 10N sodium hydroxide in 40 ml of methanol was stirred at room temperature for 1 hour and poured into 500 ml of water. After extraction with ethyl acetate, the aqueous layer was acidified with 3 N hydrochloric acid. The title compound precipitated and was collected by suction filtration, washed with water and crystallized from a mixture of methanol: chloroform 7: 3. Yield: 2.55 g, m.p. 272-277 ° C.

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (2-thienyl) -4H-1-benzopyran (Intermediate LXXXII)

This compound was prepared in two steps according to the methods indicated for intermediate LXXX, except that intermediate XCI was used instead of intermediate XC. The title compound was sown after crystallization from isopropanol melting at 116-118 ° C.

8-Carboxy-3-methyl-4-oxo-2- (2-thienyl) -4H-1-benzopyran (Intermediate LXXXIII)

This compound was prepared by the method described for intermediate LXXXI, except that intermediate LXXXII was used instead of intermediate LXXX. Melting point: 287 to 294 ° C after crystallization from a mixture of methanol and chloroform 7: 3.

8-Carboxy-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate LXXXIV)

A mixture of 1 g of 8-methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate XCII),

2.2 ml of 12.5 N sodium hydroxide, 15 ml of methanol and 5 ml of dioxane were stirred at room temperature for 2½ hours. After evaporation in vacuo, water was added until it completely dissolved and this solution was extracted with chloroform. The separated aqueous phase was acidified with dilute hydrochloric acid until a crude substance was completely precipitated, which was filtered off and purified by crystallization from acetic acid. Yield: 0.62 g, m.p. 302 ° C.

(E) -8-Ethoxycarbonyl-3-methyl-4-oxo-2- (2-styryl) -4H-1-benzopyran (Intermediate LXXXV)

This compound was prepared in three steps according to the methods described for intermediate XC (first stage) and intermediate LXXX (second and third steps). In the first step, (E) -cinamoyl chloride was used instead of 2-furoyl chloride, and the obtained (E) -ethyl 2-hydroxy- (2-styryl-propionyl) -benzoate was used for the second stage without purification. The title compound melted at 129-130 ° C after crystallization from isopropanol.

(E) -8-Carboxy-3-methyl-4-oxo-2-styryl-4H-1-benzopyran (Intermediate LXXXVI)

This compound was prepared by the methods described for intermediate LXXXI, except starting from intermediate LXXXV instead of intermediate LXXX, and maintaining the reaction mixture at room temperature for 10 hours. The title compound was sown after crystallization from melting ethanol at 284 to 286 ° C.

8-Carboxy-3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran (Intermediate LXXXVII)

A mixture of 1.9 g of 2-hydroxy-3-propionyl-benzoic acid (prepared as described in Brit. 1,343,119, 1974), 5.2 g of anhydrous sodium 4-methylbenzoate and 3.9 ml

4- methylbenzoyl chloride was stirred at 185 to 195 ° C for 8½ hours. After cooling to room temperature, the solid was allowed to stand overnight with 100 ml of chloroform. The mixture was then shaken with 5% aqueous sodium carbonate solution, which was added until the pH of the aqueous phase reached 8.9. The organic phase was extracted again with 3% sodium carbonate and the aqueous phase combined, repeatedly extracted with diethyl ether and acidified with 10 N hydrochloric acid. The precipitate was purified by flash chromatography on silica gel eluting with chloroform: methanol 100: 2 to 100: 20. The title compound, obtained by evaporating the combined fractions containing it in vacuo, melted at 249 to 251 ° C after crystallization from ethanol.

8-Ethoxycarbonyl-2- (4-fluorophenyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXVIII)

This compound was prepared in three steps according to the methods described for intermediate XC (first stage) and intermediate LXXX (second and third steps). In the first step, at room temperature, ethyl 2- (4-fluorobenzoyloxy) -3-propionyl-benzoate was obtained. This compound was used without purification for the second stage. The title compound melted at 128-130 ° C after rinsing with diethyl ether and crystallization from ethanol.

8-Carboxy-2- (4-fluorophenyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXIX)

A solution of 3.3 g of LXXXVIII intermediate and 0.6 g of lithium hydroxide hydrate in 50 ml of tetrahydrofuran, 10 ml of methanol and 10 ml of water was maintained at room temperature for 5 hours and then poured into 300 ml of 1N hydrochloric acid. The resulting precipitate was collected by suction, washed with water and dried to give 2.3 g of the title compound which, after crystallization from 95% ethanol, melted at 249-250 ° C.

Ethyl 2- (2-furoyloxy) -3-propionyl-benzoate (Intermediate XC)

4.35 ml of 2-furoyl chloride was added dropwise at 10 to 15 ° C while stirring to a mixture of 8.9 g of ethyl 2-hydroxy-3-propionyl-benzoate and 5.4 g of 4-dimethylaminopyridine in 25 ml of dichloromethane. After 2 hours at room temperature, the reaction was quenched with 200 ml of water. The organic layer was washed with 5% sodium bicarbonate, dried on anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether: ethyl acetate 4: 1 to give 9.4 g of the title compound as a low melting point solid, which was used in the next step without further purification.

NMR Spectrum at 60 MHz (CDC1 ₃ , δ)

8.2 (1H, dd, CH in position 4 of the benzene ring)

8.0 (1H, dd, CH in position 6 of the benzene ring)

7.7-7.8 (1H, dd, CH in position 5 of the furan ring)

7.43 (1H, t, CH in position 5 of the benzene ring)

7.45 (1H, s, CH in position 3 of the furan ring)

6,6-6,8 (1H, m, CH in position 4 of the furan ring)

4.3

2.9 (2H, q, COOCH ₂ CH ₃ ) (2H, q, COCH ₂ CH ₃ )

0.95 to 1.35 (m, 6H, 2xCH ₃₎

Ethyl 3-propionyl-2- (2-thienylcarbonyloxy) -benzoate (Intermediate XCI)

This compound was prepared by the method described for intermediate XC, except that 2-thienylcarboxylic acid chloride was used instead of 2-furoyl chloride.

NMR Spectrum at 60 MHz (CDC1 ₃ , δ)

7.1-8.35 (6H, m, aromatic CHs)

4.25 (2H, q, COOCH ₂ CH ₃ )

2.9 (2H, q, COCH ₂ CH ₃ )

0.95-1.3 (6H, m, 2x0 ^)

8-Methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate XCII)

A mixture of 16.8 ml of methyl thiosalicylate, 25.6 ml of ethyl benzoyl acetate and 360 g of polyphosphoric acid was stirred at 90 ° C for 3 hours. After cooling to room temperature, the mixture was poured onto crushed ice and the crude material was collected by filtration, washed with water and purified by crystallization from ethanol. Tal. 170-171 ° C.

Elemental analysis for C ₁₇ H ₁₂ O ₃ S:

Calculated (%): C 68.90; H, 4.08; S, 10.82.

Found (%): C 68.59; H, 4.13; S, 10.69.

NMR Spectrum at 200 MHz (CDC1 ₃ , δ)

8.83-8.95 (dd, 1H, benzothiopyran CH in 5)

8.45-8.53 (dd, 1H, benzothiopyran CH v 7)

7.68-7.80 (m, 2H, 2-phenyl CHs in 2 and 6)

7.55-7.65 (t, 1H, benzothiopyran CH v 6)

7.45-7.55 (m, 3H, 2-phenyl CHs in 3.4 and 5)

7.24 (s, 1H, benzothiopyran CH v 3)

4.00 (s, 3H, COOCH ₃ )

8-Ethoxycarbonyl-3-bromomethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XCIII)

A mixture of 9.2 g of 8-ethoxycarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described by Da Re, P. et al., J. Med. Pharm. Chem., 2 , 263,1960), 6.4 g of N-bromosuccinimide and 0.04 g of benzoyl peroxide in 80 ml of anhydrous carbon tetrachloride were stirred at reflux for 1½ hours. After cooling to room temperature, the resulting succinimide was collected by suction and washed with cold carbon tetrachloride. The mother liquors were evaporated in vacuo to dryness and the residue was rinsed with diethyl ether and collected by suction filtration to give 9.2 g of the title compound which, after crystallization from acetonam-hexane, melted at 133 to 134 ° C.

8-Ethoxycarbonyl-3-acetoxymethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XCIV)

A solution of 10.2 g of sodium acetate trihydrate in 30 ml of water was added dropwise at room temperature to a solution of 29 g of intermediate XCIII in 300 ml of dimethylformamide. After stirring at 50 ° C for 1½ hours, the reaction mixture was poured into 21 water and the precipitated title compound was collected by suction filtration and crystallized from acetone to give 20 g (two crops collected), m.p. Mp 151-152 ° C.

8-Carboxy-3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XCV)

116 ml of 1N sodium hydroxide was added over 10 minutes while stirring to a suspension of 14.8 g of intermediate XCIV in 300 ml of 95% ethanol. The reaction mixture was then heated at 60 to 65 ° C for 15 minutes to give a clear solution which was maintained at room temperature for another 1 hour. After evaporation in vacuo, the residue was dissolved in 200 ml of water and acidified by slow addition of 10 ml of hydrochloric acid (d = 1.18). After stirring at room temperature for 1 hour, the title compound was collected by suction filtration, washed with water and crystallized from isopropanol to give 9.3 g, m.p. (225) 237-240 ° C.

Ethyl 2- (4-nitrobenzyloxy) -3-propionyl-benzoate (Intermediate XCVI)

The title compound was prepared by the procedure described for intermediate XC, except that 4-nitrobenzoyl chloride was used instead of 2-furoyl chloride. The product was obtained as a low melting point solid (mp (40) 78-80 ° C).

NMR Spectrum at 60 MHz (CDC1 ₃ , δ)

7.85-8.50 (m, 6H, aromatic CHs)

7.50 (t, 1H, CHs in position 5 of the phenolic ring)

4.25 (q, 2H, CH ₂ O)

3.95 (q, 2H, CH ₂ )

0.95-1.30 (m, 6H, CH ₃ )

8-Ethoxycarbonyl-3-methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran (Intermediate XCVII)

A mixture of 29.7 g of XCVI intermediate and 10.18 g of anhydrous potassium t-butoxide in 89 ml of anhydrous pyridine was stirred at 100 ° C for 13 hours. The reaction mixture was cooled to room temperature, poured into 400 ml of 4N hydrochloric acid and extracted with dichloromethane. The organic layer was washed several times with water, then with 2.5% sodium hydrogen carbonate, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The crude product was purified by silica gel column chromatography eluting with hexanoethyl acetate 7: 3. Evaporation of the collected fraction in vacuo gave 7 g of the title compound, which melted at (130) 145-148 ° C.

8-Carboxy-3-methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran (Intermediate XCVIII)

A suspension of 0.38 g of XCVII intermediate in 4.75 ml of dioxane and 4.75 ml of methanol was stirred at 50 ° C. 1.29 ml of 1N sodium hydroxide was added and stirring was continued for 3 hours at the same temperature. The reaction mixture was cooled to room temperature and 3N hydrochloric acid was added until the pH was 1. The suspension was filtered by suction to give 0.13 g of the title compound, which was crystallized from 320 to 321 ° C after crystallization from dioxane.

8-Ethoxycarbonyl-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (Intermediate XCIX)

3.16 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene were added dropwise at 0 ° C with a syringe while stirring to a mixture of 3 g of ethyl 2-hydroxy-3-propionyl-benzoate in 5.53 ml. trifluoroacetic acid anhydride. The reaction mixture was stirred at 60 ° C for 4 hours; then it was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with 1N sodium hydroxide and water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 95: 5 to give 0.8 g of the title compound.

NMR Spectrum at 200 MHz (CDC1 ₃ , δ)

8.41; 8.37 (2dd; 2H, CHs in positions 5 and 7 of the benzopyran ring)

7.51 (t, 1H, CH at position 6 of the benzopyran ring)

4.46 (q, 2H, COOCHJ

2.22-2.27 (m, 3H, J _HF = 2.16 Hz, CH ₃ at position 3 of the benzopyran ring)

1.39 (t, 3H, CH ₂ CH ₃ )

8-Carboxy-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (Intermediate C)

The title compound was prepared by the same method as intermediate LXII except that intermediate XCIX was used instead of intermediate LXI and, after dilution with water, was extracted with ethyl acetate instead of filtration. After drying on anhydrous sodium sulfate and evaporating the organic layer to dryness in vacuo, the title compound was obtained as a solid, which melted at 175 to 178 ° C.

3- [4- (2-Methoxyphenyl) -1-piperazinyl1-N-methyl-propylamine (Intermediate CI) ml of 35% aqueous methylamine was added to a solution of 8.2 g of 3- [4- (2methoxyphenyl) -1- piperazinyl] -propyl chloride in 48 ml of dimethylformamide. The mixture was heated at 60 ° C in a sealed container for 5 hours and then cooled to 30 ° C. The solvent was evaporated in vacuo and the residue was stirred for 30 minutes with 100 ml of diethyl ether. The solids collected by suction filtration were dissolved in 200 ml of chloroform: 5N methanolic ammonia 100: 3. After stirring at room temperature for 30 minutes, the solution was adsorbed on a chromatographic column eluted with chloroform: 5N methanolic ammonia with a gradient of 100: 5 to 100: 15. The fractions containing the title compound were combined and evaporated in vacuo to give 3 g of intermediate CI as a thick oil.

NMR Spectrum at 60 MHz (DMSO-d ₆ , δ)

6.80 (s, 4H, aromatic CHs)

3.75 (s, 3H, OCHJ

3.20-2.75 (m, 4H, piperazine CH ₂ in position 3.5)

2.75-2.10 (m, 8H, piperazine CH ₂ in position 3.6 and CH ₂ CH ₂ CH ₂ )

2.40 (s, 1H, NH)

2.30 (s, 3H, NCH3)

1.80-1.40 (m, 2H, CH ₂ CH ₂ CH ₂ )

Ethyl 2-benzoyl-3-ethylbenzoiblfuran-7-carboxylate (Intermediate CII)

A mixture of 11.1 g of ethyl 2-hydroxy-3-propionyl-benzoate, 9.9 g of phenacyl bromide, 6.9 g of anhydrous potassium carbonate and 200 ml of acetone was stirred at reflux for 7 hours. After cooling to room temperature, the inorganic salts were separated by filtration and the solution was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with toluene. The title compound obtained by evaporation of the combined fractions containing it in vacuo was crystallized from 90% ethanol. Yield: 9.8 g, m.p. 64 to 66 ° C.

7-Carboxy-2-benzoyl-3-ethyl-benzoiblfuran (Intermediate CIII)

A mixture of 7 g of CII intermediate, 275 ml of 0.95N sodium hydroxide and 400 ml of dioxane was stirred at reflux for 4 hours. After cooling to room temperature, the dioxane was evaporated in vacuo and replaced with an equal volume of water. After charcoal filtration, the solution was acidified with dilute hydrochloric acid and the precipitate filtered and purified by crystallization from acetone. Yield: 4.94 g, m.p. 193 to 195 ° C.

Methyl 3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran-8-carboxylate (Intermediate CIV)

This compound was prepared in three steps according to the methods described for intermediate XC (first stage) and intermediate LXXX (second and third steps).

In the first step, 4-methylbenzoyl chloride was used instead of 2-furancarbonyl chloride and methyl 2-hydroxy-3propionylbenzoate was used instead of ethyl 2-hydroxy-3-propionylbenzoate. The reaction was continued at room temperature for 4 hours to give methyl 2- (4-methylbenzoyloxy) -3-propionylbenzoate. This compound was used without purification by column chromatography for a second step, which lasted 1.5 hours at 100 ° C. In the third stage, 96% sulfuric acid was used instead of 37% hydrochloric acid.

The title compound was sown after crystallization from melting ethanol at 174 to 175 ° C.

Ethyl 2- (4-biphenyl) -3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate (Intermediate CV)

This compound was prepared in three steps according to the methods described for intermediate XC (first stage) and intermediate CIV (second and third stage).

In the first step, 4-phenylbenzoyl chloride was used instead of 2-furancarbonyl chloride and the reaction lasted 20 hours at room temperature and 13 hours at reflux. Purification was performed by silica gel column chromatography eluting with petroleum ether ethyl acetate at a gradient of 100: 5 to 100: 10 to give ethyl 2- (4-biphenyl) -3-propionylbenzoate.

The title compound melted at 165 to 167 ° C after rinsing with 95% ethanol.

2- (4-Biphenyl) -3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (Intermediate CVI)

A mixture of 4.3 g of intermediate CV and 35 ml of 35% hydrochloric acid in 50 ml of 1,4 dioxane and 15 ml of water was stirred at reflux for 16 hours.

After cooling, the mixture was poured into 200 ml of water and extracted with ethyl acetate. The organic layer was separated and extracted with 20% aqueous sodium carbonate.

The precipitate formed after acidification of the aqueous layer with dilute hydrochloric acid was collected by suction, washed with water and dried to give 2.5 g of the title compound, which melted at 242.5 to 244 ° C.

2- (4-Hydroxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (Intermediate CVII)

A mixture of 3 g ethyl 2- (4-methoxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate (prepared as described in JP 58,225,083; CA 100.191648h (1984) and 60 ml 48% - of hydrobromic acid in 80 ml of acetic acid was stirred at reflux for 8 hours After cooling, the mixture was poured into 500 ml of water and the precipitate was collected by suction and washed with water, the crude material was purified by flash chromatography eluting with chloroform-isopropyl alcohols with a gradient of 9: 1 to 7: 3, followed by elution with methanol to give 1 g of the title compound, which melts at 300 ° C.

1- (2-Methoxyphenyl) -4- (4-methylaminobutyl) piperazine (Intermediate CVIII)

A solution of 3.8 ml of trifluoroacetic acid anhydride in 25 ml of anhydrous dichloromethane was added dropwise while stirring at 0 ° C to a solution of 2.53 g of 4- [4 (2-methoxyphenyl) -1-piperazinyl] butylamine in 25 ml of anhydrous dichloromethane.

After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give 3.3 g of pure 1- (2-methoxyphenyl) -4- (4trifluoroacetylamino) butylpiperazine as indicated by the NMR spectrum.

NMR Spectrum at 60 MHz (CDCl / δ))

7,70-8,00 (bs, IH) NH 6,80-7,20 (m, 4H) aromatic CHs 3.85 (s, 3H) ch ₃ o 2,90-3,80 (m, 12H) piperazine CH _{2 -} , CH ₂ N and CH ₂ NHCO 1.50-2.05 (m, 4H) c-ch ₂ ch ₂ -c

0.88 g of 50% sodium hydride was added in portions while stirring at 0 ° C to a solution of 3.3 g of the above intermediate in 46 ml of anhydrous dimethylformamide. After stirring for 1 hour at the same temperature, 0.57 ml of methyl iodide was added.

The reaction mixture was stirred at 0 ° C for 1.5 hours, then poured into water and then extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo to give 1.13 g of crude 1- (2methoxyphenyl) -4- [4- (N-methyltrifluoroacetylamino) butyl] piperazine which was taken up in the next stage was used without further purification. To a solution of 1.13 g of this intermediate in 30 ml of ethanol was added 0.18 g of sodium borohydride and the resulting mixture was stirred at 60 ° C for 1 hour.

After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo to give 0.82 g of the pure title compound.

NMR Spectrum at 60 MHz (CDC1 ₃ , (δ))

6,80-7,20 (m, 4H) aromatic CHs 3.85 (m, 3H) ch ₃ o 2,90-3,20 (m, 4H) piperazine CH ₂ s, the position 3 and 5 2.30-2,80 (m, 8H) piperazine CH ₂ s, position 2 and 6; 2xCH ₂ N 2.50 (s, 3H) ch ₃ n 1.80 (s, 1H) NH 1,40-1,80 (m, 4H) c-ch ₂ -ch ₂ -c

1- (3-amino-2,2-dimethylpropyl) -4- (2-methoxyphenyl) -piperazine

The title compound can be prepared by treating 1- (2-methoxyphenyl) -piperazine with isobutyraldehyde, 37% formaldehyde in water and acetic acid at 90 to 150 ° C, or using the same in ethanol hydrochloride (Mannich reaction) to give l- ( 2-Formyl 2-methylpropyl) -4- (2-methoxyphenyl) -piperazine, which is then aminated by treatment with excess ammonia under reducing conditions. They may be hydrogen and a catalyst (e.g., palladium on carbon, Raney nickel or platinum dioxide) in a solvent (e.g. ethanol, methanol, isopropanol, dichloromethane, chloroform or dimethylformamide) at a temperature between room temperature and 80 ° C, or alternatively a metal hydride (eg sodium borohydride, sodium or potassium cyanoborohydride or sodium triacetoxyborohydride) in a solvent (eg methanol, ethanol, chloroform, benzene or 1,2 dichloroethane) in the presence of an acid (eg hydrochloric acid or acetic acid).

It can be reacted with 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in the manner described below in Example 12 to give 8- (2,2-dimethyl-3- [4- (2-Methoxyphenyl) 1-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

8-Trifluoroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound can be prepared by the procedure described for intermediate XXIII, but using intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-benzopyran. It can be used instead of intermediate XXIII as starting material in the reaction described in Example 32 to give 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylaminomethyl} -3-methyl-4-oxo-2- phenyl-4H-1-benzopyran.

8- (2-Chloroethylureidomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This intermediate can be prepared by the method described for the preparation of intermediate XLIV, but using intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H1-benzopyran. It can be reacted with a compound of formula H-B according to the route (a) to give the desired final compounds.

8-ethenylsulfonylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound can be prepared by reacting intermediate XXIV with

2- chloroethylsulfonyl chloride in a halogenated solvent such as dichloromethane in the presence of triethylamine at 0 to 40 ° C according to A.A. Goldberg, J. Chem. Soc., 464, 1945. It can be digested with suitable H-B compounds according to the route (m) to give the corresponding final compounds. If we do as described above but start with 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, we can get the final compounds Η '^ ό-ΐΟΗ ^ -Β.

8-chlorosulfonylmethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This intermediate can be prepared by reacting 8-amidinothiomethyl-3-methyl4-oxo-2-phenyl-4H-1-benzopyran (the synthesis of which is described in intermediate XXI) with chlorine gas in water at -10 to +10 ° C in according to TB Johnson et al., J. Chem. Soc., 61.2548,1939. By metabolizing this intermediate with suitable A-NH-Z-B compounds according to path n, the desired final compounds can be obtained.

EXAMPLES

EXAMPLE 1

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran hydrochloride

A solution of 11.5 g of 1- (2-methoxyphenyl) -piperazine in 30 ml of methanol was added dropwise at 20 to 25 ° C by stirring to a mixture consisting of 21.4 g of intermediate VI and 4.1 g of potassium carbonate in 120 ml of methanol. After stirring for 4 hours at the same temperature, the volatiles were removed from the reaction mixture in vacuo. The residue was extracted with chloroform and the organic solution was washed with water, dried over anhydrous sodium sulfate / calcium chloride, filtered and the volatiles removed in vacuo. The crude product obtained was dissolved in acetone and a small excess of ethanol was added. After being collected by suction filtration and recrystallization from 95% ethanol, 16.3 g of the title compound, m.p. (189)

Mp 195-199 ° C.

EXAMPLE 2

8- {2- [4- (2-methylphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

This compound was prepared according to Example 1 except that 1- (2-methylphenyl) piperazine was used instead of 1- (2-methoxyphenyl) -piperazine and the reaction was carried out for 1 hour in dimethylformamide instead of 4 hours in methanol.

Tal. (194) 203-206 ° C (isopropanol).

EXAMPLE 3

8- {2- [4- (2-Ethoxyphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

This compound was prepared according to Example 1 except that 1- (2-ethoxyphenyl) piperazine was used instead of 1- (2-methoxyphenyl) -piperazine and the reaction was performed in dimethylformamide for 2 hours instead of methanol for 4 hours.

Tal. 208-210 ° C (isopropanol).

EXAMPLE 4

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-oxopropyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran hydrochloride

A solution of 10 ml of 37% formaldehyde in 15 ml of methanol was added dropwise over 3 minutes at 0 ° C to a solution of 5.75 g of 1- (2-methoxyphenyl) -piperazine in 10 ml of methanol. After 12 hours at 0 ° C, the volatiles were removed from the mixture in vacuo and redissolved in 15 ml of methanol. At 0 ° C, 20 ml of 3.6 N hydrogen chloride in diethyl ether was added. After evaporation of the volatiles in vacuo, the residue was suspended in 15 ml of 1,4-dioxane. While stirring at 20 to 25 ° C, a solution of 8.3 g of intermediate V in 100 ml of 1,4-dioxane was added. After stirring at reflux for 8 hours, the reaction mixture was cooled to 30 to 40 ° C. 50 ml of methanol were added and the mixture was refluxed for 2 hours. After cooling to 20 to 25 ° C, the resulting solution was diluted with 300 ml of diethyl ether. Stirring was continued for 3 hours at the same temperature. The title compound was collected by suction filtration and recrystallized from ethanol. Yield: 4 g, m.p. 209-210 ° C.

EXAMPLE 5

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dihydrochloride

A mixture of 4.24 g of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 6.3 g of anhydrous potassium carbonate in 60 ml of dimethylformamide was stirred at 80 ° C for 30 minutes. 5.23 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine were added and stirring was continued at 80 ° C for 3½ hours. The reaction mixture was cooled to room temperature, poured onto ice water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was taken up in ethanol and an excess of ethanol hydrogen chloride was added to the solution. Yield: 8.16 g of the title compound, m.p. Mp 198-203 ° C.

EXAMPLE 6

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dihydrochloride

We worked as described in Example 5, except that 1- (2-chloroethyl) -4- (2100 methoxyphenyl) -piperazine was used instead of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine to give the title compound, m.p. 200 to 203 ° C from ethanol.

EXAMPLE 7

8- {3- [4- (2-Chlorophenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran dihydrochloride

A mixture of 2.8 g of 1- (2-chlorophenyl) -piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at room temperature for 15 minutes. 4.81 g of intermediate I was added and stirring continued for 2 days. The reaction mixture was then poured into 200 ml of cold water and extracted with diethyl ether and ethyl acetate. The organic extracts were washed successively with aqueous sodium chloride solution, 0.1 N acetic acid, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water and then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound was recrystallized from acetonitrile. Yield: 3.6 g, m.p. 138 to 143 ° C.

EXAMPLE 8

8- [3- (4-Phenyl-1-piperazinyl) -propoxycarbonyl] -3-methyl-4-oxo-2-phenyl-4H1-benzopyran dihydrochloride

The title compound was prepared according to the method described in Example 7, except that 1-phenyl-piperazine was used instead of 1- (2-chlorophenyl) -piperazine hydrochloride. Recrystallization was carried out from methanol; the melting point was 229-231 ° C.

EXAMPLE 9

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran dihydrochloride

We worked as described in Example 7, except that we used 1- (2-methoxyphenyl) piperazine hydrochloride instead of 1- (2-chlorophenyl) -piperazine hydrochloride to give the title compound. This represents an alternative route to the product of Example 5.

101

EXAMPLE 10

8 {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -2-methyl-2-propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

5.29 g of XXVIII intermediate in 25 ml of 1,2-dichloroethane was added dropwise at 60 ° C to a solution of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 22 ml. 1,2-dichloroethane. The reaction mixture was refluxed for 16 hours and then cooled to room temperature and poured into a cold solution of 0.5 N sodium hydroxide. Water and dichloromethane were added. The organic phase was separated, washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvents were evaporated and the oily residue was purified by flash chromatography on silica gel, eluting with petroleum ether: ethyl acetate 85:15. The combined fractions were evaporated to dryness in vacuo and the residue dissolved in ethanol. An excess of ethanol hydrochloride was added to give 6.71 g of the title compound, m.p. 203 to 204 ° C.

EXAMPLE 11

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dihydrochloride hemihydrate

A mixture of 6.28 g of 1- (2-methoxyphenyl) -piperazine and 5.34 g of intermediate XXXVII was heated at 180 ° C for 5 hours. After cooling, the dark mass was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 100: 3. The fractions containing the title compound were combined together. The solvents were removed in vacuo and the residue was dissolved in boiling ethanol. The solution was filtered, acidified with ethanol hydrochloride and allowed to stand at 20 to 25 ° C overnight. The crude product was collected by filtration and crystallized from ethanol to give 5 g of the title compound, m.p. (177) 182-186 ° C.

EXAMPLE 12

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dihydrochloride hemihydrate

A solution of 4.48 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml of chloroform was added dropwise over 10 minutes at room temperature to the solution.

102

3.74 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamine prepared as described in GB 2161807 and 1.97 g of triethylamine in 50 ml of chloroform. After stirring for 2 hours, the solution was washed first with 0.5 N hydrochloric acid, then with saturated aqueous sodium carbonate solution and finally with water. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was processed as described in Example 11 to give 6.67 g of the title compound, m.p. (177) 182-186 ° C. This represents an alternative route to the product of Example 11.

We also prepared calf salts:

monohydrochloride hydrate, m.p. 151-154 ° C, monomethanesulfonate, m.p. 162-164 ° C and (±) -hemimalate hydrate, m.p. 110-112 ° C.

In this example, the condensation of an amine, 3- [4- (2-methoxyphenyl) -1piperazinyl-propylamine, with carbonyl chloride, 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride was described. It should be borne in mind that the amine can be condensed with the corresponding free acid or the corresponding ethyl ester by heating their equimolar amounts with or without solvent. If a solvent is used, a high boiling point hydrophilic or hydrophobic solvent is used. The amine may also be condensed at room temperature with an equimolar amount of the corresponding free acid in the presence of N, N -cyclohexylcarbodiimide and 4-dimethylaminopyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran or dimethylformamide.

EXAMPLE 13

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran monohydrochloride hemihydrate

The title compound was prepared according to the method described in Example 16, except that intermediate XIV was used instead of intermediate XV and heated at 55 to 60 ° C for 32 hours. We also varied processing as follows. After the base was collected by filtration, purification was carried out by flash chromatography on silica gel, eluting with chloroform: methanol 100: 0.5 and then 100: 1. The fractions containing the title compound were combined and the solvents were removed in vacuo. The residue was crystallized from ethanol. After filtration, the solids were taken up in boiling water and sufficient dilute hydrochloric acid was added to dissolve. The crystalline salt separated on cooling and was collected by suction filtration. Tal. 119-123 ° C.

103

EXAMPLE 14

8- {3- [2- (2-Methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

We worked as described in Example 11, except that 2- (2-methoxyphenoxy) ethylamine (prepared by Augstein, J. et al, J. Med. Chem., 8, 356, 1965) was used instead

1- (2-methoxyphenyl) -piperazine, heated for 2 hours instead of 5 hours and used dichloromethammethanol 100: 5 as eluent to give the title compound. Tal. 200-202 ° C (ethanol).

EXAMPLE 15

8- [3- (4-Phenyl-1-piperazinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran monohydrochloride hemihydrate

We worked as in Example 11, except that 1-phenylpiperazine was used instead of 1- (2methoxyphenyl) -piperazine, heated for 2 hours instead of 5 hours, and used dichloromethyl methanol 100: 4 as eluent, to give the title compound. Tal. (251) 255-258 ° C on decomposition (87% ethanol).

EXAMPLE 16

8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran monohydrochloride

A mixture of 3.56 g of intermediate XV, 2.35 g of 1- (2-methoxyphenyl) -piperazine, 2.76 g of anhydrous potassium carbonate and 1.66 g of potassium iodide in 25 ml of dimethylformamide was stirred at 100 ° C for 6 hours. After cooling, the solvent was removed in vacuo and the residue taken up in 50 ml of water, stirred for 1 hour at room temperature, collected by filtration, washed with water and crystallized from 95% ethanol in the presence of a small amount of activated carbon (for discoloration). The base was dissolved in 105 ml of boiling 0.086 N hydrochloric acid. After cooling, the crystallized salt was collected by filtration to give 4.3 g of the title compound (mp 201 to 203 ° C).

104

EXAMPLE 17

8- {1-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

1.36 g of sodium borohydride was added at rats at 0 to 5 ° C to a solution of 15.5 g of the compound prepared in Example 1 in 1500 ml of methanol. After stirring for 90 minutes at 0 to 5 ° C, 3 N hydrochloric acid was added to slightly acid the reaction mixture, from which the volatiles were then expelled. The residue was shaken with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried on anhydrous sodium sulfate / calcium chloride, filtered, acidified with ethanol hydrochloride and the volatiles were removed in vacuo. After washing with diethyl ether, the crude product was crystallized from ethanol to give 9.5 g of the title compound, m.p. 248-249 ° C.

EXAMPLE 18

8- {1-hydroxy-2- [4- (2-methylphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

This compound was prepared according to Example 17, except that it was derived from the compound prepared in Example 2, rather than from the compound prepared in Example 1. Melt. 257-258 ° C (ethanol).

EXAMPLE 19

8- {1-hydroxy-2- [4- (2-ethoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

This compound was prepared according to Example 17, except that it was derived from the compound prepared in Example 3 instead of the compound prepared in Example 1. Melt. 241-242 ° C (methanol).

EXAMPLE 20

8- {1-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

This compound was prepared according to Example 17 except from the compound prepared in

105 to Example 4, instead of the compound prepared in Example 1. The crude base was purified by flash chromatography (silica gel, eluent - ethyl acetate: chloroform 4: 1). The fractions containing the pure base were combined, acidified with ethanol hydrochloric acid and the volatiles were expelled under vacuum. The residue was crystallized from ethanol. Tal. (126) 156-160 ° C.

EXAMPLE 21

8- {1-hydroxy-4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride monohydrate

A solution of 3.04 g of intermediate XXXVIII and 2.45 g of 1- (2-methoxyphenyl) -piperazine in 21 ml of anhydrous dimethylformamide was stirred for 5 hours at room temperature. 1.22 g of 1- (2-methoxyphenyl) -piperazine were added and the mixture was stirred for 4 hours, poured into 300 ml of water and extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate solution and then with aqueous sodium chloride solution and evaporated in vacuo to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 95: 5. The volatiles were expelled from the combined fractions on a rotary evaporator and the residue was dissolved in 0.81 M ethanol hydrochloric acid and the volatiles were again expelled under vacuum. The solid residue was crystallized from water: ethanol 9: 1 to give 2.43 g of the title compound, m.p. 144 to 146 ° C.

EXAMPLE 22

8- {1-Ethoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride ml of anhydrous dimethylsulfoxide was added under nitrogen to 6.55 g of sodium hydride (50% in mineral oil, repeatedly washed with hexane). A solution of 3 g of the compound prepared in Example 17 in 50 ml of anhydrous dimethyl sulfoxide was added to the mixture at 20 to 25 ° C. After stirring at 20 ° C for 1 hour, 0.66 g of ethyl bromide was added. The reaction mixture was stirred for another 20 minutes at the same temperature and then poured onto ice water. The crude product obtained after suction filtration was purified by flash chromatography (silica gel, eluent chloroform: ethyl acetate 8: 2). The fractions containing the pure title compound were combined, acidified with ethanol hydrochloric acid and the volatiles were removed in vacuo. The residue was crystallized from

106 chloroform: diethyl ether and dried in vacuo at 140 ° C to give 1.6 g of the title compound, m.p. (155) 209 ° C.

EXAMPLE 23

8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran dihydrochloride hemihydrate

A mixture of 5.2 g of intermediate XXVII, 3.1 g of 1- (2-methoxyphenyl) -piperazine and 2.2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred at 70 ° C for 7 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 98: 2. The title compound was obtained by converting it with ethanol hydrochloride to a salt. Tal. 217 to 219 ° C.

EXAMPLE 24

8- {N-acetyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran hydrochloride

A mixture of 5 g of intermediate XXXIII and 5.3 g of 1- (2-methoxyphenyl) -piperazine in 75 ml of dimethylformamide was stirred at 95 ° C for 2 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 200 ml of water, basified with potassium carbonate and extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 100: 0.2. Conversion of the pure base with ethanol hydrochloride to salt and recrystallization from methanol gave 4.4 g of the title compound, which melted at (200) 227-228 ° C and contained one equivalent of methanol.

EXAMPLE 25

8- [4- (2-Methoxyphenyl) -1-piperazinylacetamidomethyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

107

A mixture of 3.42 g of intermediate XXXII, 2.74 g of 1- (2-methoxyphenyl) -piperazine and 0.71 g of anhydrous potassium carbonate in 34 ml of anhydrous dimethylformamide was stirred at 0 ° C for 2 hours. The reaction mixture was poured into water and filtered by suction. The resulting solid was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 6: 4. The collected fractions were evaporated to dryness in vacuo and the residue was crystallized from ethyl methyl ketone. The resulting base was treated in ethanol solution with the mole equivalent of aqueous 2.25 N hydrochloric acid to give the title compound, m.p. Mp 168-170 ° C.

EXAMPLE 26

8- {N-methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] -acetamidomethyl} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

A mixture of 5 g of intermediate XXXI, 2.9 g of 1- (2-methoxyphenyl) -piperazine and 2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred at 20 to 25 ° C for 3 hours. The reaction mixture was then poured into 500 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 6: 4 and crystallized from acetone to give 3.6 g of the base of the title compound, which melted at 144 to 145 ° C. The base was dissolved in ethanol and 8 N hydrochloric acid and water were added to give the title compound, m.p. 218-220 ° C after drying at 100 ° C in vacuo.

EXAMPLE 27

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran dihydrochloride

A mixture of 4 g of intermediate XVIII, 2.4 g of 1- (2-methoxyphenyl) -piperazine, 1.96 g of potassium iodide and 1.65 g of anhydrous potassium carbonate in 40 ml of anhydrous dimethylformamide was stirred at 90 ° C for 7 hours. After cooling to room temperature, the mixture was poured into water and extracted with dichloromethane. The combined extracts were washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was crystallized from ethyl acetate and the crystals collected were dissolved in ethanol and treated with excess ethanol hydrogen chloride to give 5.21 g of the title compound, m.p. 199-201 ° C.

108

EXAMPLE 28

8- {2- [2- (2-Ethoxyphenoxy) -ethylamino] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

We worked as in Example 27, except that 2- (2-ethoxyphenoxy) -ethylamine was used instead of 1- (2-methoxyphenyl) -piperazine and included the purification step by flash chromatography on silica gel eluted with ethyl acetate: methanol 97 : 3, to give 4.25 g of the title compound. Tal. 191-193 ° C.

EXAMPLE 29

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylthiomethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran hydrochloride

2.5 g of potassium carbonate, 2.13 g of potassium iodide and 3.15 g of 1- (2-methoxyphenyl) piperazine were added to a solution of 5 g of intermediate XXI in 50 ml of dimethylformamide and the mixture was stirred for 4 90 hours at 90 ° C. After cooling to room temperature, the reaction mixture was poured into 450 ml of water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. A solution of the residue in acetone was treated with a mole equivalent of 3.8 N hydrochloride in diethyl ether, filtered and recrystallized from ethanol to give 6.15 g of the title compound, m.p. (218) 223-224 ° C.

EXAMPLE 30

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfinylmethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dihydrochloride hemihydrate

The title compound was prepared according to the method described in Example 29, using intermediate XXVI instead of intermediate XXI and stirring for 2½ hours instead of 4½ hours. After normal processing, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 97: 3. The collected fractions were acidified with excess ethanol hydrogen chloride and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 5.2 g of the title compound, m.p. 170-172 ° C. This compound contains 1 equivalent of ethanol.

109

EXAMPLE 31

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfonylmethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

A mixture of 4.5 g of intermediate XXV, 2.36 g of 1- (2-methoxyphenyl) -piperazine and 0.84 g of potassium carbonate in 45 ml of anhydrous dimethylformamide was stirred at room temperature for 2½ hours. The reaction mixture was poured into 300 ml of water and filtered off with suction, washing with water. The solid base was crystallized from ethanol and had a melting point of 143-146 ° C. The crystallizate was dissolved in 1,2-dichloroethane and acidified with ethanol hydrochloride. Recrystallization from methanol: water 1: 3.5 gave 4.4 g of the title compound, m.p. 229-233 ° C.

EXAMPLE 32

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylamino} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran dihydrochloride

A solution of 3.7 g of intermediate XXIII in 10 ml of dimethylformamide was added dropwise at 0 ° C to a suspension of 0.9 g of sodium hydride (50% in mineral oil) in 9 ml of dimethylformamide. The cooling bath was removed and a solution of 4.1 g of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine in 10 ml of dimethylformamide was added after 30 minutes at 20 to 25 ° C. The mixture was stirred at 90 ° C for 5 hours and then cooled to 20 to 25 ° C. A further 0.25 g of sodium hydride (25% in mineral oil) was added followed by 1.36 g of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine in 5 ml of dimethylformamide. The mixture was stirred at 90 ° C for 8 hours and cooled again to 20 to 25 ° C. 200 ml of water were carefully added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with n-hexane: ethyl acetate 3: 2. A mixture of the base of the title compound and the corresponding N-trifluoroacetyl compound was thus obtained.

3.8 g of this mixture were dissolved in 35 ml of ethanol and 35 ml of dimethylsulfoxide. 0.55 g of sodium borohydride was added portionwise at 20 to 25 ° C to this solution. The mixture was stirred for 3 hours at this temperature, then poured into 200 ml of water and extracted with ethyl acetate. The organic extracts were washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was dissolved in dichloromethane.

110

2 equivalents of ethanol hydrochloride were added to give the title compound, which was recrystallized from ethanol. Yield: 3.8 g, m.p. 231-234 ° C.

EXAMPLE 33

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran hydrochloride 2.75-hydrate

Using 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine instead of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine, otherwise working as described in Example 32, gave the title compound. Tal. 206-208 ° C (10% ethanol).

EXAMPLE 34

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylamino} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride hemihydrate

A mixture of 4.5 g of intermediate XXXIX, 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8.3 g of sodium triacetoxyborohydrate and 3.4 ml of acetic acid in 40 ml 1, The 2-dichloroethane was stirred for 6 hours at 20 to 25 ° C. Then 15 ml of 5% aqueous sodium bicarbonate solution was added and the mixture was stirred for 10 minutes. The mixture was then basified by the addition of 0.5 N sodium hydroxide solution and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 9: 1. The resulting base was dissolved in dichloromethane and 1 equivalent of ethanol hydrogen chloride was added. After removal of the solvent in vacuo, the residue was crystallized from 50% ethanol to give 1.6 g of the title compound, m.p. (140) 151-153 ° C.

EXAMPLE 35

8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran hydrochloride hemihydrate

A mixture of 4 g of the compound prepared in Example 33 in the form of its base, 4.35 ml of 37% aqueous formaldehyde and 1.15 g of sodium cyanoborohydride in 25 ml of acetonitrile was stirred at 20 to 25 ° C, by adding acetic acids during the reaction

111 maintained the pH in the range of 5 to 6. After 4 hours, the solvent was evaporated in vacuo. To the residue was added 80 ml of ethyl acetate and 200 ml of ice-cooled 1 N sodium hydroxide solution. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 3: 1. The pure base obtained was dissolved in diethyl ether. One equivalent of ethanol hydrogen chloride was added and the solvent removed in vacuo. The residue was crystallized from water to give 2 g of the title compound, m.p. 186-187 ° C.

EXAMPLE 36

8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran hydrochloride hydrate

A mixture of 4.8 g of the compound prepared in Example 33 as its base, 2.8 ml of acetic anhydride and 33 ml of pyridine was stirred at 80 ° C for 4 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 200 g of ice water, acidified with 10 N hydrochloric acid and extracted with dichloromethane. The organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 95: 5. The pure base obtained was dissolved in dichloromethane. 1 equivalent of ethanol hydrogen chloride was added and the solvent was removed in vacuo. The residue was crystallized from acetonitrile to give 3 g of the title compound containing 0.33 equivalent of acetonitrile, m.p. 208.5 to 210.5 ° C.

EXAMPLE 37

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propionamido} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran hydrochloride

A mixture of 3.97 g of intermediate X and 3.07 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was stirred at 60 ° C for 6 hours. The reaction mixture was then cooled to room temperature and poured into water. After extraction with dichloromethane, the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The crude residue was crystallized from ethanol to give the base of the title compound, which was then dissolved in hot ethanol. One molar equivalent of 0.81 M ethanol was added to the solution. 4 g of the title compound were obtained,

112 tal. Mp 255-257 ° C.

EXAMPLE 38

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylureido} -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulfonate

A mixture of 3.34 g of intermediate XLIV and 7.22 g of 1- (2-methoxyphenyl) -piperazine was stirred at 100 ° C for 5 hours. An additional 1.8 g of 1- (2-methoxyphenyl) -piperazine was then added and stirring was continued for 2 hours at 100 ° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydroxide solution, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 98: 2. The collected fractions were evaporated to dryness in vacuo and crystallized from water: ethanol 4: 6. The crystals were redissolved in dichloromethane and treated with 1 mole equivalent of methanesulfonic acid. The crude methanesulfonate obtained by evaporation in vacuo was crystallized from ethyl acetate: ethanol 1: 1 to give 2.35 g of the title compound, which melted at 191 to 193 ° C.

EXAMPLE 39

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

A mixture of 6.61 g of intermediate XI, 8.34 g of 1- (2-methoxyphenyl) -piperazine and 1.26 g of sodium iodide in 70 ml of dimethylformamide was stirred at 80 ° C for 17 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 600 ml of water, basified with 5% aqueous sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 99: 1 and then 98: 2. The fractions containing the base of the title compound were combined and the solvent removed in vacuo. The residue was dissolved in ethanol and ethanolic hydrogen chloride was added. The title compound, which was collected by suction filtration, crystallized. It was recrystallized from 95% ethanol. Yield: 6.5 g, m.p. 224-225 ° C.

113

Elemental analysis:

Found: C 66.38 H 6.34, N 5.35, C16.76, H ₂ O3.35

Calc. %: C 66.34, H 6.14, N 5.33, 06.75, H ₂ 0 3.43

NMR Spectrum at 60 MHz (CDC1 ₃ -CD ₃ OD)

7.8- 7.1 (m, 8H, aromatic protons of the benzopyran ring)

7.1-6.6 (m, 4H, aromatic protons of the 2-methoxyphenyl group)

4.8- 4.4 (m, 2H, OCH ₂₎

4.4-4.1 (m, 3H, H ₂ O and N ⁺ H)

3.9- 3.0 (m, 10H, 5 x CH ₂ N)

3.8 (s, 3H, OCH ₃ )

2.1 (s, 3H, CH ₃ )

EXAMPLE 40

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran dihydrochloride

This compound was prepared according to the method described in Example 29 except that intermediate IX was used instead of intermediate XI. Purification by flash chromatography was abandoned because it was unnecessary in this case. Tal. 226-227 ° C.

EXAMPLE 41

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran dihydrochloride

A mixture of 7.75 g of intermediate XVI, 4.7 g of 1- (2-methoxyphenyl) -piperazine, 3.3 g of potassium iodide and 2.8 g of anhydrous potassium carbonate in 78 ml of dimethylformamide was stirred at 75 ° C for 2 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 600 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate. The pure title compound obtained as its base was converted by treatment with ethanol hydrochloride to its dihydrochloride. Crystallization from ethanol gave 6.5 g of the title compound. Tal. 217-219 ° C.

114

EXAMPLE 42

8- {5- [4- (2-Methoxyphenyl) -1-piperazinyl] -pentyloxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

This compound was prepared according to the method described in Example 41, except that intermediate XVII was used instead of intermediate XVI. Tal. 173 C (ethanol). The corresponding base was melted at 117 to 118 ° C (ethanol).

EXAMPLE 43

8- {3- [4- (2-Methoxyphenyl) -1-oxo-1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran 1,75-hydrate

2.93 g of magnesium monoperoxyphthalate in 10 ml of water were added dropwise at -15 ° C to a solution of 4.34 g of the compound prepared in Example 40 and 0.1 g of benzyl (triethyl) ammonium chloride in 20 ml of dichloromethane and 20 ml methanol. The mixture was stirred for 2 hours at 0 ° C and then warmed to room temperature. It was poured into water and made alkaline by the addition of aqueous sodium hydroxide solution. Extraction with dichloromethane gave, after conventional treatment, a solid which was purified by flash chromatography eluting with dichloromethane: methanol 9: 1. The collected fractions containing the pure compound were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give 0.5 g of the title compound, m.p. 89 to 92 ° C.

EXAMPLE 44

8- {2- [2- (2,6-Dimethoxyphenoxy) -ethylamino] -ethoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

A mixture of 4.5 g of intermediate XII, 3.7 g of triphenylphosphine and 2.85 g of 2,6-dimethoxyphenoxyacetaldehyde (prepared by Nelson, WL et al., J. Med. Chem., 22, 1125, 1979) was mixed in 45 ml of benzene. at 20 to 25 ° C for 18 hours and at reflux for 5 hours. The solvent was evaporated in vacuo and the residue was dissolved in 80 ml of anhydrous methanol. A molecular sieve with 3x10 ' ⁷ mm was added. Then 0.61 g of sodium borohydride was added at 0 ° C. The mixture was allowed to stand for 1 hour at 0 ° C and for 1 hour at 20 to 25 ° C and then poured into ice water and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate. We're solvent

115 was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 49: 1. The resulting base was treated with ethanol hydrochloride. Crystallization from ethanol gave the title compound. Yield: 40%, m.p. 200-202 ° C.

EXAMPLE 45

8- {2-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran hydrochloride

A solution of 3.7 g of intermediate XL and 4.64 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was stirred at 80 ° C for 3 hours. After cooling to 20-25 ° C, the reaction mixture was poured into 400 ml of water and extracted with dichloromethane. The aqueous phase was basified with 1 N sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvents were evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate. The fractions containing the title compound in the form of its base were combined and the volatiles were evacuated. The residue was dissolved in dichloromethane and 1 equivalent of ethanol was added. The solvents were removed in vacuo and the residue was crystallized from ethanol. 5 g of the title compound were obtained which contained 1 molar equivalent of ethanol. Tal. (122) 126-128 ° C at decomposition.

EXAMPLE 46

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylthio} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran

A mixture of 4.4 g of intermediate XXXIV, 2.5 g of 1- (2-methoxyphenyl) -piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide were stirred at 100 ° C for 3 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 350 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate and the solvent was then evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 3: 2 and crystallization from ethanol to give 3.9 g of the title compound, m.p. (70) 96-99 ° C.

116

EXAMPLE 47

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran hydrochloride

A solution of 3.8 g of intermediate XXXV and 4 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was heated at 60 ° C for 7 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate and the solvent was then evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 1: 1. We got the base of the title compound. It was dissolved in ethanol and one equivalent of ethanol hydrogen chloride was added to give 4.5 g of the title compound, m.p. (215) 226-228 ° C.

EXAMPLE 48

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

A solution of 4.5 g of intermediate XLII and 3.8 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was heated at 70 ° C for 7 hours. After cooling to 20 to 25 ° C, the reaction mixture was poured into 150 ml of water and extracted with dichloromethane. The organic solution was washed with water and dried over anhydrous sodium sulfate and the solvent was then evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3: 7, and the title compound obtained by conversion to ethanol with hydrogen chloride. Yield: 2.9 g, m.p. 236-238 ° C.

EXAMPLE 49

8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran hydrochloride

The title compound was obtained by the method described in Example 48, except that intermediate XLI was used instead of intermediate XLII. Tal. 194-198 ° C (ethanol).

117

EXAMPLE 50

8- {N-Carbamoyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate hemihydrate

A mixture of 4.06 g of the compound of Example 33 and 1.5 g of potassium cyanate in 42 ml of glacial acetic acid was stirred at 50 ° C for 4 hours. The reaction mixture was poured into ice water and basified. The precipitate was collected by suction filtration, dried and purified by flash chromatography using a silica gel column and eluting with ethyl acetate: methanol 98: 2. The fractions containing the title compound as a base were evaporated to dryness in vacuo and one methanesulfonic acid equivalent was added to the residue after dissolution in 30 ml of dichloromethane. The solvent was evaporated in vacuo and the residue was crystallized from ethanol to give 3.1 g of the title compound (mp 157-160 ° C at decomposition). This compound contained one molar equivalent of ethanol.

EXAMPLE 51

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-oxobutyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate

A solution of 1.33 ml of anhydrous dimethyl sulfoxide in 9 ml of dichloromethane was added at -70 ° C to a solution of 0.74 ml of oxalyl chloride in 6 ml of dichloromethane. After stirring at -70 ° C for 15 minutes, a solution of 2.8 g of the compound of Example 21 (as a base) in 14 ml of dichloromethane was added. After 15 minutes at the same temperature, 4.7 ml of anhydrous triethylamine was added and the temperature was raised to -30 ° C for 30 minutes. Stirring was continued at -30 ° C for another 30 minutes. After allowing the temperature to rise to 0 ° C, the mixture was diluted with 120 ml of water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate: dichloromethane 9: 1. The fractions containing the title product as a base were evaporated to dryness in vacuo and one methanesulfonic acid equivalent was added to the residue after dissolution in 30 ml of dichloromethane. The solvent was evaporated in vacuo and the residue was crystallized from ethanol to give 2.9 g of the title compound, m.p. Mp 194-195 ° C.

118

EXAMPLE 52

8- {3- [2- (1,4-benzodioxanyl) methylamino] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate

A mixture of 5.56 g of intermediate XLIII as base, 4.58 g of 2- (p-toluenesulfonyloxymethyl) -1,4benzodioxane and 1.9 g of anhydrous potassium carbonate in 80 ml of anhydrous dimethylformamide was stirred at 110 ° C for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography using a silica gel column eluting with ethyl acetate: methanol 95: 5. The fractions containing the title compound as a base were evaporated to dryness in vacuo. The residue was dissolved in ethanol and one equivalent of methanesulfonic acid dissolved in ethyl acetate was added. The crystallized product was filtered off and recrystallized from ethanol to give 2.4 g of the title compound, m.p. 172 to 174 ° C.

EXAMPLE 53

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulfonate

A solution of 2.8 g of intermediate XLVI and 0.13 g of p-toluenesulfonic acid in 150 ml of methanol was refluxed for 5 hours. After cooling to 20-25 ° C, 0.8 g of anhydrous potassium carbonate was added and stirring continued for 3 hours. After filtration, the reaction mixture was evaporated to dryness in vacuo to give 2.5 g of 8- (4,4-dimethoxybutyl) 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

NMR (CDCl ₃ , S)

1.6-1.9 (4H, m, CHCH ₂ CH ₂ CH)

2.2 (3H, s, flavonic CH ₃ )

2.9 (2H, t, FT-CH2)

3.3 (6H, s, 2 x OCH ₃ )

4.4 (1H, t, CHCOCH ^ J

7.3 (1H, dd, flavone CH in 6)

7.5-7.8 (6H, m, flavone CH in 7 and 5 x phenyl CH)

8.1 (1H, dd, flavone CH in 5)

119

A solution of 2.5 g of the compound thus prepared in 10 ml of water and 30 ml of acetic acid was heated at 50 ° C for 2½ hours. The reaction mixture was cooled to room temperature, diluted with ice water, basified with aqueous sodium carbonate and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether: ethyl acetate 3: 1. 2.1 g of 8- (4-oxobutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (> 75% yield) were obtained, which was used without further purification in the next step .

NMR (CDCl ₃ , δ)

1.9-2.1 (2H, dd, CH ₂ CH ₂ CH ₂ CHO)

2.2 (3H, s, flavonic CH ₃ )

2.5 (2H, t, CH ₂ CHO)

2.9 (2H, t, F1'-CH ₂₎

7.3 (IH, dd, flavone CH v 6)

7.5-7.7 (6H, m, flavone CH in 7 and 5 x phenyl CH)

8.1 (1H, dd, flavone CH in 5)

9.7 (1H, s, CHO)

2.3 ml of 6 N hydrochloric acid in ethanol, a solution of 2.1 g of the compound thus prepared in 40 ml of methanol and 0.45 g of sodium cyanoborohydride were added sequentially to a solution of 8 g of 1- (2-methoxyphenyl) -piperazine in 30 ml of methanol. After stirring for 24 hours at room temperature, the reaction mixture was poured into 500 ml of ice water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was purified by flash chromatography using a silica gel column eluting with ethyl acetate: petroleum ether 9: 1. The fractions containing the title product as a base were evaporated to dryness in vacuo. The residue was dissolved in 30 ml of dichloromethane and one equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the residue was crystallized from acetone to give 2.35 g of the title compound (m.p. 141-143 ° C).

EXAMPLE 54

8- [3- (4-Phenyl-1-piperidinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulfonate

This compound was prepared according to the method described in Example 11, using

120

4-phenylpiperidine instead of 1- (2-methoxyphenyl) -piperazine and the reaction was run for 1 hour instead of 5 hours. Purification was performed by flash chromatography using a silica gel column eluting with dichloromethane: methanol 100: 5. Tal. Mp 157-159 ° C (ethyl acetate). Appropriate base of melting session at (127) 147-149 ° C (ethanol).

EXAMPLE 55

8- [3- (4,4-Diphenyl-1-piperidinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulfonate

This compound was prepared according to the method described in Example 11, except that 4,4-diphenylpiperidine was used instead of 1- (2-methoxyphenyl) -piperazine and the reaction was carried out for 2 hours instead of 5 hours. Tal. 221-223 ° C (ethyl acetate).

EXAMPLE 56

8- {3- [4- (4-Fluorobenzoyl) -1-piperidinyl] -propyl-carbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared according to the method described in Example 11, except that 4- (4fluorobenzoyl) -piperidine was used instead of 1- (2-methoxyphenyl) -piperazine and the reaction was carried out for 30 minutes instead of 5 hours. Purification was carried out by flash chromatography using a silica gel column eluting with dichloromethane: 5N methanolic ammonia with a gradient of 1: 1 to 100: 20. Tal. 181-183 ° C (ethanol).

EXAMPLE 57

8- {3- [4- (2-Oxo-1-benzimidazolinyl) -1-piperidinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared according to the method described in Example 11, using 4- (2-oxo-1-benzimidazolinyl) -piperidine instead of 1- (2-methoxyphenyl) -piperazine. Purification was performed by flash chromatography using a silica gel column eluting with chloroform: 5N methanolic ammonia 100: 3. Tal. 238-241 ° C (ethanol).

121

EXAMPLE 58

8- {3- [4- (2-Pyrimidinyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran methanesulfonate

The title compound was prepared according to the method described in Example 11, using 1- (2-pyrimidinyl) -piperazine instead of 1- (2-methoxyphenyl) -piperazine and reacted for 2 hours. The product was purified by flash chromatography using a silica gel column eluting with chloroform: methanol 100: 3. The desired fractions were dissolved in dichloromethane and one equivalent of methanesulfonic acid was added to the solution. After evaporation of the solvent in vacuo, the residue was boiled for 1 hour with ethyl acetate and then collected by filtration. Tal. 209-210 ° C. The product contained 0.2 equivalents of ethyl acetate and 0.1 equivalents of water. Appropriate melting session base at 178-180 ° C (ethanol).

EXAMPLE 59

8- {3- [4- (2-hydroxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran

We worked as described in Example 11, except that we used 1- (2-hydroxyphenyl) piperazine instead of 1- (2-methoxyphenyl) -piperazine, heated for 1½ hours instead of 5 hours, and used dichloromethane: methanol 100: 3 to 100: 10 as eluent for column chromatography to give the title compound. Tal. 118-120 ° C (95% ethanol).

EXAMPLE 60

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate

This compound was prepared according to the method used in Example 12 except that 4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamine was used instead of 3- [4- (2-methoxyphenyl) -1piperazinyl-propylamine. The reaction mixture was stirred at room temperature for 22 hours, diluted with water and filtered by suction, washing the insoluble solids with water. The crude residue was dried and purified by silica gel column chromatography eluting with ethyl acetate: methanol 9: 1. Fractions containing pure product as a base were collected, evaporated to dryness in vacuo and dissolved

122 in dichloromethane. Methanesulfonic acid was added to the solution, and the salt was precipitated by adding two volumes of ethyl acetate, filtered and recrystallized from ethanol to give the title compound, m.p. Mp 230-232 ° C. This product contained 0.3 molar equivalent of ethanol.

EXAMPLE 61

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylsulfamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate

This compound was obtained by working as described in Example 12, except that intermediate VIII was used instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran and stirred for 24 hours instead of 2½ hours . The crude product was purified by silica gel column chromatography eluting with ethyl acetate: methanol 98.5: 1.5. The collected fractions containing the pure product as a base were evaporated to dryness in vacuo and dissolved in dichloromethane. Methanesulfonic acid was added to the solution and the solvent was removed by evaporation in vacuo. The crude salt was crystallized from ethanol to give the title compound, m.p. (196) 198-200 ° C.

EXAMPLE 62

8- {3- [N-methyl-2- (2-methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A solution of 10.5 ml of 40% formaldehyde in water was added to a suspension of 6.66 g of the compound prepared in Example 14 in 55 ml of acetonitrile and 20 ml of water. After stirring at room temperature for 15 minutes, 2.70 g of 95% sodium cyanoborohydride was added to the red solution, and 1.38 ml of acetic acid were added under the same conditions for an additional 15 minutes under the same conditions. After stirring for 3 hours, the solvents were removed in vacuo and the residue was rinsed with 250 ml of water and 250 ml of chloroform. After addition of 3 N sodium hydroxide, the organic phase was separated and the aqueous phase extracted 2 times with chloroform. The solvent was removed from the collected organic phases by evaporation in vacuo and the residue was purified by flash chromatography on silica gel eluting with chloroform: 5.2 N methanolic ammonia 100: 0.5 to 100: 2. The collected fractions containing the pure title compound as a base were evaporated to dryness in vacuo and the residue was dissolved in hot ethanol. The solution was acidified with ethanol hydrochloride and after evaporation of the solvent in vacuo the residue was rinsed with diethyl ether

123 and stirred at room temperature. The crude product was collected by filtration and crystallized from acetonitrile to give 3.1 g of the title compound, m.p. Mp 146-148 ° C.

EXAMPLE 63

8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propionamido} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran methanesulfonate

We worked as described in Example 37, except that intermediate L was used instead of intermediate X and stirred at 90 ° C for 4 hours instead of 60 ° C for 6 hours to give the title compound as a crude base. Purification by silica gel column chromatography eluting with ethyl acetate: methanol 95: 5 gave crude methanesulfonate as described in Example 61 and crystallized from acetone to give the title compound, m.p. 200-202 ° C.

EXAMPLE 64

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-phenyl-4-oxo-4H-benzopyran dimethanesulfonate

The title compound was prepared by working as described in Example 12 except that LVI was used instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl4H-1-benzopyran and stirred for 24 hours instead of 2½ hours . The crude product was purified by column chromatography, eluting with ethyl acetate: methanol 92: 8, and the pure base obtained by evaporation of the collected fractions in vacuo was dissolved in dichloromethane. Two equivalents of methanesulfonic acid were added. The crude dimethanesulfonate obtained after solvent evaporation was recrystallized from acetone, m.p. 153-156 (200) ° C.

EXAMPLE 65

8- {3 - [(3,4-dihydro-1-oxo-2H-naphthyl) -methylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

A mixture of 6 g of intermediate XLIII, 2.4 g of 2-methylene-α-tetralone (prepared as described in Org. Synth., 60, 88, 1981) and 3.14 ml of triethylamine in 48 ml of anhydrous dimethylformamide were stirred at room temperature. for 6 hours and then at 50 ° C for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. Organic

The 124 layers were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue was purified 2 times by column chromatography eluting first with dichloromethane: methanol 95: 5 and then with dichloromethane: methanol: 5.8N methanolic ammonia 98: 2: 0.2 to give 1.74 g the title compounds as a base. The base was converted to methanesulfonate according to the procedure described in Example 61. The salt was recrystallized first from acetone and then from acetonitrile to give the title compound, m.p. (69) 157-159 ° C.

EXAMPLE 66

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonylmethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dihydrochloride

The title compound was prepared according to the method described in Example 5, except that intermediate XLVII was used instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1- (2-chloroethyl) -4 - (2-methoxyphenyl) -piperazine instead of 1- (3-chloropropyl) -4- (2methoxyphenyl) -piperazine. 193-196 ° C from ethanol: diethyl ether.

EXAMPLE 67

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran dimethane sulfonate

The title compound was prepared as described in Example 61 except that 4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamine was used instead of 3- (4- (2methoxyphenyl) -1-piperazinyl] -propylamine The crude dimethanesulfonate was crystallized first from acetonitrile and then from ethanol, mp 172-174 ° C.

EXAMPLE 68

8- {N- (2-tetrahydropyranyloxy) -3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate hemihydrate

A solution of 3.6 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine in 30 ml of anhydrous dimethylformamide was added dropwise while stirring at 0 ° C to a mixture of 3.92 g of O- (2-tetrahydropyranyl) -hydroxylamine (prepared as described by RN Watrener et al., Angewandte Chem. Int. Ed., 5, 511, 1966). Stirring was continued for 2 hours

125 at O ° C and then at 110 ° C for 12 hours. The reaction mixture was cooled to room temperature and the dimethylformamide was removed by vacuum distillation. The residue was washed with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give

4.39 g of 1- [3- (2-tetrahydropyranyloxyamino) -propyl] -4- (2-methoxyphenyl) -piperazine. N-NMR (CDC1 ₃ , δ)

6.50-6.75 (m, 4H, aromatic protons)

5.20

4.60 (bs, 1H, NH) (m, 1H, O-CH-O)

3.30-4.00 (m, 5H, OCH ₃ and tetrahydropyran CH ₂ O)

2.80-3.20 (m, 6H, piperazine 2 x CH ₂ , alkyl chain CH _? N)

2.20-2.80 (m, 6H, piperazine 2x CH ₂ , alkyl chain CH ₂ N)

1.30-2.00 (m, 8H, tetrahydropyran 3 x CH ₂ , alkyl chain C-CH ₂ -C)

A solution of 2.79 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 47 ml of chloroform was added dropwise at room temperature to a mixture of 3.26 g of the compound thus prepared and 1.42 g of potassium carbonate in 47 ml of chloroform. The reaction mixture was stirred for 3 hours, then diluted with 75 ml of chloroform and washed 3 times with 1M sodium hydroxide. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The crude residue was purified by silica gel column chromatography eluting with ethyl acetate: methanol 98: 2. The collected fractions were evaporated to dryness in vacuo to give 2.99 g of the pure title compound as a base. The base was dissolved in dichloromethane and methanesulfonic acid was added to the solution. The solvent was removed by evaporation in vacuo and the crude salt was crystallized from ethyl acetate to give the title compound, m.p. Mp 159-160 ° C.

EXAMPLE 69

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butyramido} -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulfonate hemihydrate

The title compound was prepared according to the method described in Example 38 except that intermediate XLVIII was used instead of intermediate XLIV and stirred for 1 hour at 70 ° C and for 2 hours at 130 ° C instead of 7 hours at 100 ° C. After normal processing, the crude residue was purified by silica gel column chromatography eluting with ethyl

126 acetate: methanol 95: 5. Fractions containing the pure title compound as a base were collected and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and one equivalent of methanesulfonic acid was added to the solution. After evaporation of the solvent in vacuo to dryness, the crude salt was crystallized from acetone, m.p. 175-176 ° C.

EXAMPLE 70

E-8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxyimino-methyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran

A solution of 5.4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 5.13 g of Lil intermediate in 10 ml of chloroform containing a molecular sieve of 3 x ^{10 7} mm was stirred at reflux for 6 hours. The molecular sieve was removed by filtration and the solution was evaporated in vacuo to dryness. The crude product was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 7: 3. Two groups of fractions were collected and evaporated to dryness in vacuo. The first eluted group of fractions (less polar) contained an almost pure title compound; the second group (more flame) was a mixture of 1: 1 E- and Z-diastereomers as determined by NMR.

NM-NMR (CDC1 ₃ , δ)

8.75 (dd, 0.5H, benzopyran CH v 7, Z)

8.65 (s, 0.5H, imine CH, E)

8.30 (dd, 1H, benzopyran CH in 5, E + Z)

8.15 (dd, 0.5H, benzopyran CH v 7, E)

8.00 (s, 0.5H, imine CH, Z)

7.60-7.75 (m, 2H, phenyl CH in 2 'and 6', E + Z)

7.50-7.60 (m, 3H, phenyl CH in 3 ', 4' and 5 ', E + Z)

7.45 (dd, 0.5H, benzopyran CH v 6, Z)

7.41 (dd, 0.5H, benzopyran CH v 6, E)

6.70-7.10 (m, 4H, phenyl protons, E + Z)

4.41 (t, 2H, CH ₂ O, E + Z)

3.86 (s, 3H, CH ₃ O, E + Z)

3.05-3.20 (m, 4H, piperazine 2 x CH ₂ , E + Z)

2.70- 2.90 (m, 6H, piperazine 2 x CH ₂ and CH ₂ N, E + Z)

2.20 (s, 1.5H, benzopyran CH ₃ in 3, Z)

2.18 (s, 1.5H, benzopyran CH ₃ in 3, E)

The E-diastereomer was crystallized from ethanol: water 2: 1 to give 2.5 g of pure Na127 hunting compound, m.p. Mp 107-109 ° C.

EXAMPLE 71

8- {N-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 0.25 H ₂ O

A solution of 2.04 g of the compound of Example 68 as a base in 104 ml of 1.6N ethanol hydrochloride was stirred for 12 hours at room temperature. The ethanol was removed by evaporation in vacuo and the residue was rinsed with 1N sodium hydroxide and dichloromethane. The organic layer was collected, washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. One molar equivalent of methanesulfonic acid was added to a solution of the residue in dichloromethane. The solvent was removed and the crude methanesulfonate was crystallized from acetone to give 1.02 g of the title compound, m.p. 211-213 ° C. The product contained 0.25 moles of water.

EXAMPLE 72

E-8- <2- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -ethenyl> -3-methyl4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 1.2 H ₂ O

The title compound was obtained by the method described in Example 61 except that Intermediate IV was used instead of Intermediate VIII and 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylamine instead of the corresponding propylamine in 1,1,2,2 -tetrachloroethylene as solvent. Finally, the reaction mixture was diluted with water and chloroform and washed with 1 N aqueous sodium hydroxide and then with water. After drying on anhydrous sodium sulfate, the organic layer was added methanesulfonic acid and the solvents were evaporated in vacuo. The crude product was crystallized 2 times from isopropanol to give the title compound containing 1.2 molar equivalents of water. Tal. 124-127 ° C.

EXAMPLE 73

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfinyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulfonate

The title compound was prepared according to Example 38 except that LIV was used instead of XLIV, stirring at 70 ° C for 3 hours and again at 90

128 ° C 3 hours after the catalytic amount (0.01 equivalent) of potassium iodide was added. Purification by silica gel column chromatography eluting with ethyl acetate: methanol 9: 1 gave the title compound as a base. Untreated bases dissolved in dichloromethane were added 1 molar equivalent of methanesulfonic acid. After removal of the solvent by evaporation in vacuo, the resulting salt was crystallized from acetone to give the title compound, m.p. 183-184 ° C.

EXAMPLE 74

8- {3- [3- (2-Methoxyphenoxy) -propylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate hemihydrate

The title compound was prepared by the method described in Example 76, except that 3- (2-methoxyphenoxy) -propyl chloride (prepared as described in B. Willhalm, Tetrahedron, 20, 1185, 1964) was used instead of 2- (2 , 6-dimethoxyphenoxy) -ethyl bromide. The extraction residue from dichloromethane was purified by silica gel column chromatography eluting with dichloromethane: methanol: 5N methanolic ammonia 9: 1: 0.3. The pure base was converted to methanesulfonate, which was crystallized

2 times from ethyl acetate: acetonitrile 9: 1 to give the title compound, which melts at (60) 87-90 ° C.

EXAMPLE 75

8- {3- [2- (2-methylthiophenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate

1.85 g of 95% sodium borohydride was added to a solution of 7 g of LIX intermediate in 70 ml of methanol, which was stirred at 0 ° C. After stirring at the same temperature for 1 hour, the solvent was removed by evaporation in vacuo. The residue was diluted with water and 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give 6.6 g of pure 2- (2-methylthiophenoxy) -ethanol as an oil. To a solution of the compound thus prepared in 35 ml of pyridine stirred at 0 ° C was added 8.57 g of p-toluenesulfonyl chloride in portions. After stirring at room temperature for 14 hours, the reaction mixture was poured into cold 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed twice with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give 7.8 g of a 3: 1 mixture of 2- (2-methylthiophenoxy) ethyl 129 p-toluenesulfonate and 2- (2- methylthiophenoxy) ethyl chloride (found by NMR) as a low melting point solid, which was used without further purification.

Homogeneous mixture 3.3 g of the above mixture and 8 g of intermediate XLIII were kept in an oil bath at 140 ° C for 20 minutes. After this time, the molten mass was cooled to room temperature and solidified. The solid residue was washed with dichloromethane and 4N sodium hydroxide. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness.

The crude product was purified by silica gel column chromatography eluting with dichloromethane: methanol 9: 1 to give 2.07 g of the title compound as a base. This was converted by the conventional method to crude methanesulfonate, which was crystallized first from acetone and then from acetonitrile. Tal. Mp 143-146 ° C.

EXAMPLE 76

8- {3- [2- (2,6-Dimethoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran hydrochloride

Homogeneous mixture of 3.3 g of 2- (2,6-dimethoxyphenoxy) -ethyl bromide (prepared as described in J. Augstein et al., J. Med. Chem., 8,356.1965) and 8.4 g of intermediate XLIII was heated on an oil bath at 150 ° C for 10 minutes. The molten mass was cooled to room temperature and solidified. The solid residue was washed with ethyl acetate and 2N sodium hydroxide. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The oily residue was purified 2 times by column chromatography on silica gel, eluting first with ethyl acetate: methanol: 5N methanolic ammonia 97: 3: 0.3 and then with dichloromethane: methanol: triethylamine 90: 10: 0.3. This gave 3.3 g of the pure title compound as a base. The crude hydrochloride obtained by the conventional method was recrystallized from acetone and then from acetonitrile. Tal. Mp 179-181 ° C.

EXAMPLE 77

8- {3- [4- (5-Chloro-2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl) -3-methyl-4-oxo-2phenyl-4H-1-benzopyran

This compound was prepared by the method described in Example 11, except that 1- (5-chloro-2-methoxyphenyl) -piperazine was used instead of 1- (2-methoxyphenyl) piperazine and the reaction was carried out for 6 hours instead of 5 hours.

130

Purification was carried out by flash chromatography on silica gel eluting with chloroform: 5N ammonia in methanol (100: 1). After crystallization from 95% ethanol, the title compound melted at 163-166 ° C.

EXAMPLE 78 (E) -8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-butenyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran

33.4 ml of 1 molar solution of lithium bis (trimethylsilyl) amide in anhydrous tetrahydrofuran was added dropwise over 15 minutes to a suspension of 6.4 g

Of 3-hydroxypropylphenylphosphonium bromide in 60 ml of anhydrous tetrahydrofuran cooled to -15 ° C. A solution of 4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml of tetrahydrofuran was then added dropwise. The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1½ hours.

Termination of the reaction with methanol followed by evaporation to dryness in vacuo gave a residue which was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 6: 4. The collected fractions were evaporated in vacuo to give 4.17 g of 8- (4-hydroxy-1-butenyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran as a mixture of E- and Z-diastereoisomers in NMR 3.5: 1 ratio.

NM-NMR, 200 MHz (CDCl ₃ , S)

8.10-8.20 (d, 1H, benzopyran CH v 5, E + Z)

7.30-7.80 (m, 7H, other flavors, E + Z)

6.80-7.00 (2d, 1H, aryl-CH =, E + Z)

6.41 (dt, 0,78H, CH-CH _2, E)

5.90 (dt, 0,22H, CH-CH _2, Z)

3.60- 3.80 (m, 2H, CH ₂ O, E + Z)

2.45-2.60 (m, 2H, CH-CH ₂ , E + Z)

2.18 (s, 3H, benzopyran CH ₃ in 3, E + Z)

1.60- 1.90 (with, 1H, OH, E + Z)

To a solution of 2.2 g of the above mixture in 24 ml of anhydrous pyridine stirred at 0 ° C was added 1.65 g of p-toluenesulfonyl chloride. Stirring was continued for 48 hours at the same temperature and the reaction mixture was then poured into cold 1N hydrochloric acid and filtered by suction. The resinous solid was washed with water and rinsed with dichloromethane. The solution was dried on anhydrous sodium sulfate and evaporated to dryness in

131 vacuum to give 2.30 g of (E, Z) -4- {8- [3-methyl-4-oxo-2-phenyl-4H-benzopyranyl} -3-butenyl p-toluenesulfonate which had the same diastereoisomize the composition as the above intermediate.

A solution of 2.85 g of p-toluenesulfonic acid ester and 2.98 g of 1- (2methoxyphenyl) -piperazine in anhydrous dimethylformamide was stirred at room temperature for 48 hours. After this time, the mixture was poured into 250 ml of water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give a residue which was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 6: 4. The collected fractions were evaporated to dryness in vacuo and the crude product was crystallized from 70% ethanol to give 1.48 g of the title compound, which melted at 119-112 ° C.

NM-NMR, 200 MHz (CDCl ₃ , δ)

8.14 (dd, 1H, benzopyran CH in 5)

7.85 (dd, 1H, benzopyran CH v 7)

7.41-7.70 (m, 5H, phenyl CHs)

7.34 (dd, 1H, benzopyran CH v 6)

6.70-7.10 (m, 5H, aryl-CH = and methoxyphenyl CHs)

6.30-6.50 (dt, 1H, J _trans = 16.5Hz, CH-CH ₂ )

3.86 (s, 3H, CH ₃ O)

3.00-3.15 (m, 4H, 2 piperazine CH ₂ )

2.50-2.80 (m, 8H, 2 piperazine CH ₂ , CHCH ₂ CH ₂ N)

2.18 (s, 3H, benzopyran CH ₃ in 3)

EXAMPLE 79 (E) -8- <2- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -ethenyl> -3-methyl-4oxo-2-phenyl-4H-1-benzopyran methanesulfonate

The title compound was prepared according to Example 6, except that intermediate III was used instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. After normal processing, the residue was crystallized 2 times from ethanol. The resulting solid was purified by silica gel column chromatography eluting with chloroform: ethyl acetate 8: 2 to give a pure base which was dissolved in chloroform: ethanol 1: 1. Methanesulfonic acid was added to the solution and the solvents were removed by evaporation in vacuo. The crude salt was crystallized from isopropanol to give the title

132 compound which melts at 193-195 ° C. This compound contains 0.33 equivalents of isopropanol and 0.25 equivalents of H ₂ O.

EXAMPLE 80

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylcarbamoylmethyl} -4-oxo-2-phenyl-4H-benzopyran methanesulfonate hydrate

A mixture of 2.8 g of intermediate XLVII and 1.28 g of l-hydroxybenzotriazole in 20 ml of anhydrous dimethylformamide was stirred at 0 to 5 ° C for 15 minutes. A solution of 1.96 g of dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide was added dropwise over 40 minutes. After stirring at room temperature for 8 hours, a solution of 2.24 g of 1- (2-aminoethyl) -4- (2-methoxyphenyl) -piperazine in 15 ml of anhydrous dimethylformamide was added. After stirring for 5 hours and overnight at room temperature, the insoluble material was filtered off and the filtrate was poured into about 300 ml of water and basified with the addition of 1N sodium hydroxide. The mixture was extracted with dichloromethane and the organic layer separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with chloroform: methanol 95: 5. To the solution of the crude base in ethanol was added 1 mole equivalent of methanesulfonic acid. Diethyl ether was added until the salt crystallized. The salt was then filtered off and recrystallized from ethanol: diethyl ether 1: 2 to give 1.15 g of the title compound, m.p. Mp 160-162 ° C.

133

EXAMPLE 81

8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A solution of 2.86 g of LVII intermediate, 5.04 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) piperazine and 2.58 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred at 90 ° C for 7 hours. After cooling to room temperature, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried on anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 7: 3 to give 1.89 g of the title compound, which melted at (55) 62-63 ° C.

EXAMPLE 82

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfonylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

1.05 ml of 2-chloroethanesulfonyl chloride were added dropwise to a solution of 5 g of 8-amino3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1.4 ml of triethylamine stirred at 0 ° C. . The reaction mixture was stirred at room temperature for 2 days. After filtering the precipitated solids, the solution was evaporated to dryness in vacuo to give a crude residue containing 8- (ethenylsulfonylamino) -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, which was used without further cleaning. A mixture of 7.54 g of this residue and 5.8 g of 1- (2-methoxyphenyl) -piperazine and 4.15 g of potassium carbonate in 100 ml of dimethylformamide was stirred at room temperature for 4 hours, poured into 600 ml of water and extracted with ethyl acetate . The organic layer was evaporated to dryness in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether: acetone 8: 2. The collected fractions were evaporated to dryness and crystallized from 70% ethanol to give 0.75 g of the title compound as a base. This solid was dissolved in dichloromethane and one equivalent of methanesulfonic acid was added to the solution. The crude methanesulfonate obtained by evaporation in vacuo was crystallized from acetone to give 0.6 g of the title compound, which melted at 202 to 203 ° C.

134

EXAMPLE 83

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylthiocarbamoyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran methanesulfonate

While stirring, a mixture of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 0.75 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) - piperazine and 0.14 g of sulfur in 5 mi of pyridine were refluxed for 6 hours. After evaporation of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with chloroform. The title compound (as a base) was dissolved in dichloromethane and one equivalent of methanesulfonic acid was added. The title compound was obtained by evaporation in vacuo and crystallization of the residue from acetonitrile. Yield: 0.7 g, m.p. Mp 189-190 ° C.

EXAMPLE 84

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran methanesulfonate. 1/4 H ₂ O

The title compound was prepared according to Example 73 except that LX was used instead of LIV. It was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 7: 3. One molar equivalent of methanesulfonic acid was added to the solution of the crude base in dichloromethane. After removal of the solvent by evaporation in vacuo, the resulting salt was crystallized from acetone to give the title compound, m.p. Mp 212-214 ° C.

EXAMPLE 85

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-hydroxymethyl-4-oxo2-phenyl-4H-1-benzopyran. 0.4 ethanol

A mixture of 3.6 g of XCV intermediate and 1.65 g of 1-hydroxybenzotriazole in 35 ml of anhydrous dimethylformamide was stirred at 0 to 5 ° C for 15 minutes. A solution of 2.5 g of dicyclohexylcarbodiimide in 35 ml of anhydrous dimethylformamide was added dropwise. After stirring for 1 hour at the same temperature, a solution of 1- (3-aminopropyl) -4- (2methoxyphenyl) -piperazine was added. After stirring for 2 hours at the same temperature and overnight at room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified by flash chromatography eluting with the mixture

135 dichloromethane: methanol 100: 3, followed by crystallization from ethanol. 2.5 g of the title compound are obtained, m.p. Mp 152-154 ° C.

EXAMPLE 86

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-benzopyran methanesulfonate. 0.25 H ₂ O

3.6 ml of diethyl cyanophosphonate were added dropwise at 0-5 ° C while stirring to a solution of 4 g of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re et al ., Ber., 99, 1962, 1966) and 3.75 g of 1- (3-aminopropyl) -4- (2methoxyphenyl) -piperazine in 35 ml of anhydrous dimethylformamide. Immediately afterwards, 2.5 ml of triethylamine were added dropwise at the same temperature. After 30 minutes of stirring at 0 to 5 ° C and 1 hour at room temperature, the reaction mixture was poured into 350 ml of 2.5% aqueous sodium carbonate. The resulting precipitate was stirred for 1 hour at room temperature, collected by suction filtration and crystallized from ethanol. The base of the title compound thus obtained was dissolved in dichloromethane and one equivalent of methanesulfonic acid was added. After evaporation in vacuo, a glassy solid was obtained which was crushed and refluxed for 1 hour in acetone to give 5 g of the title compound, which was melting at 191-194 ° C.

EXAMPLE 87

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dihydro-4-oxo-4H1-benzopyran methanesulfonate

A solution of 0.84 ml of thionyl chloride in 17 ml of anhydrous dichloromethane was added dropwise to a solution of 2.0 g of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran (prepared according to Lichtenberge et al., Buli Chem. Soc. Fr., 275.1963) and 1.75 ml of triethylamine in 17 ml of dichloromethane, which was stirred at room temperature. Stirring was continued for 1½ hours at the same temperature. After this time, the reaction mixture was evaporated to dryness to give crude 8-chlorocarbonyl-2,3-dihydro-4-oxo-4H-1-benzopyran. This was used in the method of Example 10 instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran to prepare the base of the title compound, which was purified by column chromatography eluting with ethyl acetate: methanol 85:15. The yield was 1.91 g of pure base. After dissolving in dichloromethane, acidifying with methanesulfonic acid and evaporating to dryness

136 in vacuo, the resulting crude salt was crystallized from acetonitrile to give 1.57 g of the title compound, which melted at 175-177 ° C.

EXAMPLE 88

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-1-benzopyran methanesulfonate. 1.25 H ₂ O

The title compound was prepared according to the method described in Example 87, except that intermediate LXII was used instead of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran. The crude methanesulfonate was washed with diethyl ether, filtered and repeatedly crystallized from acetonitrile. Tal. Mp 155-157 ° C.

EXAMPLE 89

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-bromo-3-methyl-4-oxo2-phenyl-4H-1-benzopyran

This compound was prepared according to Example 86, except that 8-carboxy-6-bromo-3methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in EP 107804) was used instead of 8-carboxy- 4-Oxo-2-phenyl-4H-1-benzopyran. It was purified as silica gel flash chromatography eluting with dichloromethane: methanol 100: 3 and crystallized from 95% ethanol. Tal. (150) 154-159 ° C.

EXAMPLE 90

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methoxy-3-methyl-4-oxo2-phenyl-4H-1-benzopyran methanesulfonate

1.01 ml of diethyl cyanophosphonate and 0.85 ml of triethylamine were added to a solution of 1.7 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in JP 61-15880) and 1.51 g of 1- (2-methoxyphenyl) -4- (3-aminopropyl) -piperazine in 20 ml of anhydrous dimethylformamide, stirred at 0 ° C. After stirring for 1 hour at 0 ° C to room temperature, the reaction mixture was poured into a mixture of 100 ml of water and 10 ml of 1N sodium hydroxide. The base of the title compound precipitated and was filtered off and washed with water. After drying, it was converted in the usual way to the methanesulfonate we are

137 was crystallized from acetonitrile. Yield: 1.7 g; m.p. Mp 185-186 ° C.

EXAMPLE 91

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-methyl-4-oxo2-phenyl-4H-1-benzopyran methanesulfonate

0.8 g of the compound prepared in Example 114 and 5.8 ml of 1N sodium hydroxide in 10 ml of methanol were stirred at room temperature for 4 hours. After overnight, 15 ml of 1N sodium hydroxide and 15 ml of methanol were added and the mixture was stirred at room temperature for 1 hour. The methanol was evaporated in vacuo and water was added to the residue. The suspension was filtered off by suction to give 0.48 g of the title compound base. This was converted by the usual process into its methanesulfonate salt, which was recrystallized from acetonitrile. Tal. 200-202 ° C.

EXAMPLE 92

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

The title compound was prepared according to Example 90, except that 8-carboxy-3,6 dimethyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re et al., Arch.Pharm. , 296,714,1963) instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile and and melted at 196-197 ° C.

EXAMPLE 93

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-6-nitro-4-oxo2-phenyl-4H-1-benzopyran

This product was obtained by working as described in Example 12, except that intermediate LXVIII was used instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran and 1,1,2- trichloroethane instead of chloroform. After normal processing, the crude product was purified by column chromatography eluting with dichloromethane: methanol 98: 2. Evaporation of the collected fractions in vacuo to dryness and crystallization from ethanol gave the title compound, m.p. Mp 159.5-161 ° C.

138

EXAMPLE 94

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 33 g of the compound prepared in Example 93, 109 ml of IN hydrochloric acid, 105 ml of water and 8.78 g of Raney nickel in 950 ml of ethanol was hydrogenated in a Parr apparatus at a hydrogen pressure of 1.96 bar while stirring at 40 °. C 12 hours After this time, the catalyst was filtered off and washed with 80% ethanol. The mother liquors were evaporated in vacuo to a volume of 80 ml and filtered. The crude product was washed with water and suspended in water; 37% hydrochloric acid was added until the pH was 1. The insoluble matter was filtered off by suction and the filtrate was basified by the addition of 35% sodium hydroxide. The title compound precipitated. It was collected by filtration and washed with water. Drying gave 26 g of a compound which melted at (108)

215-217.5 ° C, which was used in Example 95 without further purification. For characterization, 4.7 g of product was crystallized first from ethanol and then from 85% ethanol to give 3 g of the title compound, m.p. 218-219 ° C.

EXAMPLE 95

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was obtained by the procedure described in Example 36, except that the compound prepared in Example 94 was used instead of the compound prepared in Example 33. The reaction mixture was diluted with water and filtered by suction and the solid was washed with water. After drying at 80 ° C, the solid was purified by silica gel column chromatography eluting with chloroform: methanol 95: 5. Evaporation of the collected fractions in vacuo and crystallization of the residue from 95% ethanol gave the title compound, m.p. (150) 218-220 ° C.

EXAMPLE 96

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-ethylamino-3-methyl-4oxo-2-phenyl-4H-1-benzopyran

A mixture of 8.42 g of the compound of Example 94, 0.45 ml of acetaldehyde, 0.59 g of 85%

139 sodium cyanoborohydride and 3.3 ml 4.85N ethanol hydrochloride in 73 ml methanol were stirred at room temperature for 5 days. After this time, the reaction mixture was poured into cold 1.5N sodium hydroxide; The suspension was diluted with water and filtered by suction. After drying, the residue was purified by silica gel column chromatography eluting with chloroform: methanol 100: 3. Evaporation of the collected fractions in vacuo afforded 6 g of the compound of Example 94 and 2.67 g of the title compound which, after recrystallization from ethanol, melted at 198-201 ° C.

EXAMPLE 97

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-dimethylamino-3methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was prepared according to Example 35, except that the compound prepared in Example 94 was used instead of the compound prepared in Example 33 and the 10 molar equivalents of 40% formaldehyde were metabolised instead of 7 molar equivalents and 3 moles of sodium cyanoborohydride instead of 2 moles and stirring at room temperature for 18 hours instead of 4½ hours. After conventional treatment and purification by silica gel column chromatography eluting with chloroform: methanol 97: 3, evaporation of the collected fractions in vacuo and crystallization of the residue from ethanol, the title compound was melted at 183-186 ° C.

EXAMPLE 98

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -7-methoxy-3-methyl-4-oxo2-phenyl-4H-1-benzopyran

The title compound was prepared according to the procedure described in Example 87, except that intermediate LXIX was used instead of 8-carboxy-2,3-dihydro-4-oxo-4H-benzopyran. After usual processing, the solid residue was purified by silica gel column chromatography eluting with ethyl acetate: methanol 8: 2. The collected fractions were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give the title compound, which melted at 151-152 ° C.

EXAMPLE 99

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2140 (4-trifluoromethylphenyl) -4H-1-benzopyran methanesulfonate sesquihydrate

The title compound was prepared according to the procedure described in Example 90 except that it was derived from intermediate LXXII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran. After crystallization from acetonitrile, methanesulfonate was melted at (85), 90-120 ° C (decomposition).

EXAMPLE 100

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-1-benzopyran methanesulfonate hemihydrate

The title compound was prepared according to the procedure described in Example 90 except that it was derived from intermediate LXXIV instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile. Tal. Mp 208-210 ° C.

EXAMPLE 101

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran methanesulfonate. 0.25 H ₂ O

The title compound was prepared according to the procedure described in Example 90 but proceeded from intermediate LXXVII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2phenyl-4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile. Tal. 200-202 ° C.

EXAMPLE 102

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dimethyl-4-oxo4H-1-benzopyran

This compound was prepared according to Example 86, except that 8-carboxy-2,3-dimethyl-4-oxo-4H-1-benzopyran (prepared according to Da Re, Farmaco Ed. Sci., 11, 678, 1956) was used instead of 8- carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was carried out at room temperature for 5 hours. It was purified by flash chromatography on silica gel eluting with chloroform: methanol 98: 2 and crystallized from acetone. Tal.

141

155-158.5 ° C.

EXAMPLE 103

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (t-butyl) -3-methyl4-oxo-4H-1-benzopyran dihydrochloride dihydrate

This compound was prepared according to Example 86, except that intermediate LXXVIII was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. The base was purified by flash chromatography on silica gel eluting with chloroform: methanol 49: 1 and converted to the dihydrochloride in methano.diethyl ether. After recrystallization from methanol: diethyl ether 1: 1, it melts at 226-229.5 ° C.

EXAMPLE 104

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-cyclohexyl-3-methyl-4oxo-4H-1-benzopyran

This compound was prepared according to Example 86, except that intermediate LXXIX was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was carried out for 5 hours at room temperature. It was purified by flash chromatography on silica gel eluting with chloroform: methanol 49: 1 and crystallized from acetonitrile (mp 155157 ° C).

EXAMPLE 105

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (2-furyl) -3-methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86 except that intermediate LXXXI was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was carried out at room temperature for 5 hours. After termination of the reaction, the title compound was isolated by chloroform extraction and purified by flash chromatography on silica gel, eluting with chloroform: methanol 49: 1, followed by crystallization from acetonitrile. Tal. Mp 151-153 ° C.

142

EXAMPLE 106

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-thienyl4H-1-benzopyran

This compound was obtained according to Example 86 except that intermediate LXXXIII was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. It was purified by stirring in water (to remove dimethylformamide completely), followed by column chromatography on silica gel, eluting with chloroform: methanol 49: 1 and crystallizing from acetonitrile. Tal. 174-175 ° C.

EXAMPLE 107

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-benzothiopyran

A mixture of 2.8 g of intermediate LXXXIV and 3.4 g of Ι, Γ-carbonyldiimidazole in 60 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature for 1½ hours. 2.7 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) -piperazine were then added. After stirring at room temperature for 2 hours, the reaction mixture was poured into 300 ml of water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with chloroform: methanol 49: 1, washed with water and crystallized from acetonitrile to give 2 g of the title compound, which melted at 144-146 ° C.

EXAMPLE 108 (E) -8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo- (2-styryl) -4H-1-benzopyran

This compound was prepared according to Example 86, except that intermediate LXXXVI was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. It was purified by crystallization from acetonitrile. Tal. 191-194 ° C.

143

EXAMPLE 109

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, except that intermediate LXXXVII was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and digested at room temperature for 4 hours. After termination of the reaction, the title compound was isolated by extraction with ethyl acetate, dried over anhydrous sodium sulfate and evaporated in vacuo, then rinsed with diethyl ether and crystallized from acetonitrile. Tal. 161-163 ° C.

EXAMPLE 110

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-methoxyphenyl) -3methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, except that 8-carboxy-2- (4methoxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran (prepared as described in EP 108986) was used instead of 8-carboxy- 4-oxo-2-phenyl-4H-1-benzopyran and digested at room temperature for 3½ hours. It was purified by flash chromatography on silica gel, eluting with chloroform: methanol 49: 1, followed by crystallization from acetonitrile. Tal. Mp 158-161 ° C.

EXAMPLE 111

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-fluorophenyl) -3methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86 except that 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran was used as an intermediate. It was purified by flash chromatography on silica gel eluting with chloroform: methanol 100: 2 to 100: 6 and crystallized from 95% ethanol. Tal. 166-168 ° C.

EXAMPLE 112

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanesulfonylamino3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

144

0.032 ml of methanesulfonyl chloride in 1 ml of dimethylformamide were added dropwise over 10 minutes to a solution of 0.21 g of the compound of Example 94 and 0.062 ml of triethylamine in 4 ml of dimethylformamide, which was stirred at -20 ° C. Stirring was continued at the same temperature for 3½ hours. After this time, the reaction mixture was poured into water and the suspension filtered by suction to give 0.1 g of the title compound, which was recrystallized from 80% ethanol. Tal. Mp 272-275 ° C.

EXAMPLE 113

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-2- (4-nitrophenyl) 4-oxo-4H-1-benzopyran

The title compound was prepared according to the procedure described in Example 90 except from the XCVIII intermediate instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2phenyl-4H-1-benzopyran. After stirring at room temperature for 1 hour, the reaction mixture was poured into cold 2% sodium carbonate solution and the precipitated solid was collected by suction filtration. After drying and crystallizing from ethanol, the title compound melted at (60) 185-187 ° C.

EXAMPLE 114

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-diethoxyphosphonyloxy-3methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was prepared according to the procedure described in Example 90 except starting from intermediate LXIII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran and using 2 equivalents of diethyl cyanophosphate instead 1.1 equivalents. Filtration from water gave the title compound, which melted at 48 to 80 ° C (decomposition). The title compound can be considered a prodrug of 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

EXAMPLE 115

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran methanesulfonate. 2/3 H ₂ O

145

We proceeded as described in Example 90 but proceeded from intermediate C instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran to give the crude base of the title compound. After conventional treatment with ethyl acetate extraction, the residue was purified by silica gel column chromatography eluting with ethyl acetate: methanol 9: 1. According to the usual procedure, it was converted to its methanesulfonate and recrystallized from ethyl acetate. Tal. 145-148 ° C.

EXAMPLE 116

8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was prepared according to Example 12, except that intermediate CI was used instead

3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylamine. The crude base was purified by flash chromatography on silica gel eluting with chloroform: 5N methanolic ammonia 100: 1 and converted to hydrochloride in the usual way. Tal. 195-198 ° C after crystallization from acetone.

EXAMPLE 117

7- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-benzoyl-3-ethyl-benzo [b] furan

This compound was prepared according to Example 86, except that intermediate CIII was used instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and digested at room temperature for 4 hours. It was purified by crystallization from ethanol. Tal. Mp 165-166 ° C.

EXAMPLE 118

2- (4-biphenyl) -8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl4-oxo-4H-1-benzopyran

The title compound was prepared according to Example 86 except that a CVI intermediate was used instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The digestion took 20 hours at room temperature.

The base was purified by crystallization from ethanol (mp 164-166 ° C).

146

EXAMPLE 119

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-2- (3pyridyl) -4H-1-benzopyran

A mixture of 6.2 g of methyl 3-propionylsalicylate and 5.8 g of nicotinoyl chloride hydrochloride in 18 ml of anhydrous pyridine was stirred and heated at 100 ° C for 2 hours under hydrogen. Then, 16 ml of triethylamine was added and the heating was continued for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, poured into 600 ml of water and the precipitate collected by suction and washed with water to give 5.4 g of methyl 2-hydroxy-3- (2nicotinoyl) propionylbenzoate, which was used in the next step without cleaning.

3.4 g of this intermediate was heated at 100 ° C for 1.5 hours after being dissolved in a mixture containing 15 ml of acetic acid and 1 ml of 37% hydrochloric acid.

After cooling to room temperature, the mixture was poured into 150 ml of water and extracted with ethyl acetate. The organic phase was washed with 5% aqueous sodium hydrogen carbonate and then with water, dried over sodium sulfate and evaporated in vacuo to give 1.3 g of crude methyl 3-methyl-4-oxo-2- (3-pyridyl). -4H-1-benzopyran-8carboxylate.

g of the above ester was dissolved in 9 ml of methanol and 15 ml of 1,4-dioxane and 1.7 ml of 10 N sodium hydroxide was slowly added while maintaining the temperature between 20 and 25 ° C. After 1 hour at 50 ° C, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid. The precipitate was collected by suction to give 0.6 g of 3-methyl-4-oxo-2- (3-pyridyl) 4H-1-benzopyran-8-carboxylic acid, which was used in the next step without Purification.

The title compound was prepared according to Example 86 except that the above intermediate was used instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and the reaction was carried out for 2 hours at room temperature. The base was purified by flash chromatography on silica gel, eluting with a mixture of chloroform: methanol 98: 2 followed by crystallization from acetone to give 0.15 g (mp 134.5 to 137 ° C).

EXAMPLE 120

8- {3- [4- (2-Acetoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-1-4-oxo-2phenyl-4H-1-benzopyran g compound of Examples 59 and 0.32 g 4- of dimethylaminopyridine was dissolved in 10 ml of dik147 loromethan and 0.15 ml of acetyl chloride was slowly added while maintaining the temperature between 8 and 10 ° C.

After 2 hours at room temperature, the reaction mixture was poured into 70 ml of water and extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate and then with water, dried on anhydrous sodium sulfate and evaporated in vacuo.

The crude base was purified by flash chromatography on silica gel, eluting with a 9: 1 mixture of ethyl acetate: methanol, followed by crystallization from ethanol to give 0.74 g of the title compound (mp 120-123 ° C).

EXAMPLE 121

3-methyl-8- {3- [4- (2-methylaminocarbonyloxyphenyl) -1-piperazinyl] -propylcarbamoyl} 4- oxo-2-phenyl-4H-1-benzopyran compound of Example 59 and 1.8 ml of methylisocyanate were prepared dissolved in 30 ml of dry N, Ndimethylformamide and stirred at room temperature for 24 hours.

The mixture was diluted with water, stirred for 2 hours and then filtered by suction.

The crude base was purified by flash chromatography on silica gel eluting with chloroform: 5N ammonia in methanol (100: 3). The title compound melted at 132 to 135 ° C after crystallization from ethanol.

EXAMPLE 122

6-acetoxy-8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran

0.17 ml of acetyl chloride was added dropwise over 5 minutes while stirring at 0 ° C to a solution of 1 g of the compound of Example 91 and 0.32 ml of triethylamine in 36 ml of chloroform. After stirring for 2 hours at the same temperature, the reaction mixture was diluted with dichloromethane and water. The organic layer was separated, washed with water, dried on sodium sulfate and evaporated in vacuo to dryness.

Crystallization of the acetonitrile residue gave 0.8 g of the title compound, which melted at 148-149 ° C.

148

EXAMPLE 123 (R, S) -2,3-Dihydro-4-hydroxy-8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -4H-1-benzopyran methanesulfonate

The title compound was prepared by the same method as described in Example 17 except that it was derived from the compound of Example 87 instead of the compound of Example 1.

The reaction mixture was diluted with water and stirred for 15 minutes. It was then extracted with ethyl acetate. Conventional processing gave a crude substance which was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 95: 5.

Evaporation of the collected fractions in vacuo gave a pure base which was converted to methanesulfonate and crystallized from acetonitrile (m.p. 172-175 ° C).

EXAMPLE 124

2- (4-aminophenyl) -8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3methyl-4-oxo-4H-1-benzopyran

2.22 g of the compound of Example 113 and 0.56 g of Raney nickel in 96 ml of ethanol and 4.8 ml of acetic acid were hydrogenated in a Parr apparatus (pressure H ₂ 0.98 bar) at room temperature.

After shaking for 6 hours, the catalyst was filtered off and the filtrate was basified with 3N sodium hydroxide and diluted with water.

After 2 days of standing, the precipitated title compound was collected by suction, washed with water, dried and recrystallized first from ethyl acetate and then from ethanol to give 1.5 g (mp 192-194 ° C).

EXAMPLE 125

2- (4-acetylaminophenyl) -8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3methyl-4H-1-benzopyran

The title compound was prepared by the same method as that described for the compound of Example 36, except that the compound prepared in Example 124 was used instead of the compound of Example 33.

It was purified by crystallization from 95% ethanol (mp 207-209 ° C).

149

EXAMPLE 126

2- (4-hydroxyphenyl) -8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3methyl-4H-1-benzopyran dihydrochloride monohydrate

The title compound was prepared according to the method described in Example 86 except that CVII was used instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and the reaction was carried out for 14 hours at room temperature even in the presence of hexamethylphosphorylamide as co-solvents.

The isolated diethylphosphonyl ester of the title compound was hydrolyzed by alkaline treatment followed by neutralization with dilute hydrochloric acid. The crude base was extracted with chloroform and the organic layer was washed with water and evaporated in vacuo. The salt was prepared by adding ethanol hydrogen chloride to the acetone solution of the base, evaporating to dryness and rinsing with acetone (mp 193-205 ° C).

EXAMPLE 127

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -2-phenyl-4, N, N _4- trixo-4H-1-benzothiopyran monohydrate

To 0.8 g of the compound of Example 107 and 15 ml of acetic acid were added 0.32 ml of 30% hydrogen peroxide and stirred at 50 ° C for 3 hours. Then 0.48 ml of 30% hydrogen peroxide (3 x 0.16 ml after every 2 hours of heating) was added to the mixture. After cooling, the mixture was poured into 240 ml of water, neutralized with 5% aqueous sodium hydrogen carbonate at pH 7 and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 0.18 g of the title compound which, after crystallization from acetonitrile, melted at 172 to 175 ° C.

EXAMPLE 128

7- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -2-phenylbenzo [b] furan

The title compound was prepared according to the method described in Example 86, except that 2-phenylbenzo [b] furan-7-carboxylic acid (prepared as described in EP 306,226 (1989)) was used instead of 4-oxo-2-phenyl- 4H-1-benzopyran-8-carboxylic acid, and the reaction was carried out at room temperature for 1.5 hours.

It was purified by crystallization from carbon tetrachloride (mp 132-136 ° C).

150

EXAMPLE 129

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propyl-N-methylsulfamoyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran methanesulfonate

2.29 g of intermediate VIII were added portionwise to a solution of 1.5 g of intermediate CI and 0.95 g of triethylamine in 30 ml of chloroform while stirring at 0 ° C.

After stirring for 2 hours at room temperature, the reaction mixture was diluted with dichloromethane, water and 0.5 N sodium hydroxide. The organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo to dryness.

The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 96: 4. Inflammation of the collected fractions in vacuo gave the pure title compound as a base. This was converted by the conventional method to a methanesulfonate salt, which was crystallized from ethyl acetate to give 2.75 g of salt, which melted 135 to 141 ° C (decomposition).

EXAMPLE 130

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] butyl-N-methylsulfamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

The title compound was obtained by the same method as described in Example 129 but using CVIII instead of CI.

The title compound was crystallized from acetonitrile (mp 173-175 ° C).

151

PHARMACOLOGICAL INFORMATION

Methodology

Male Sprague Dawley rat [Crl: CD 'BR] weighing 200 to 300 g, Albino Swiss female mouse [Crl: CD-I (ICR) BR] weighing 20 to 30 g and male dogs of English marriage (body weight 10 up to 12 kg) was obtained from Charles River, Italy, resp. Nossana (Correzzana, Milan, Italy). Animals were housed with free access to food and water and kept on a forced cycle of light and dark at 22 to 24 ° C until the day of the experiments.

Acute toxicity

Acute toxicity of the synthesized compounds was determined in albino Swiss female mice after intraperitoneal and oral administration. Four logarithmically escalated doses of the compounds were dissolved or suspended in 0.5% Methocel and given in a volume of 10 ml / kg to groups of 4 mice / dose. Mortality was recorded 7 days after administration. Data analysis: LD ₅₀ values and their confidence limits were calculated using the Weil method (Biometrics, 8,249,1952).

Receptor binding studies

Binding [~ H] prazosin receptors)

The rat cerebral cortex was homogenized in 50 volumes of the original wet mass of ice-cold 50 mM Tris-HCl buffer, pH 7.4. The homogenates were centrifuged at 48000 x g for 10 minutes and the pellets were resuspended in the same volume of ice-cold buffer and centrifuged and resuspended 2 more times. The resulting final pellets were resuspended in the same volume of buffer and incubated according to the conditions given in the table below.

The above receptor binding studies as well as the experimental data below in dogs demonstrate that the compounds of the invention are a? Blockers, i.e. that they are widely used as anti-hypertensive and anti-BPH agents. See, e.g. Frishman, W.H. et al., Medical Clinics of N. America, 72, 427, 1988 and references cited therein.

152

- Binding of [-H18-OH-DPAT (5HT _1A receptors)

The rat hippocampus was homogenized in 50 volumes of the original wet mass of ice-cold 50 mM Tris-HCl buffer, pH 7.4. The homogenates were centrifuged at 48,000 x g for 10 minutes and the pellets were resuspended in the same volume of ice-cold buffer, incubated for 10 minutes at 37 ° C, and centrifuged and resuspended 2 more times. The resulting final pellets were resuspended in the same volume of buffer and incubated according to the conditions given in the table below.

These receptor binding studies were used to determine that the compounds of the present invention are ligands for the 5HT _1A receptor. As mentioned above, compounds that are 5HT _1A ligands have anxiolytic and antidepressant effects in animals and humans (Hamon, M. et al., Ann. Ν.Υ. Acad. Sci., 600,114,1990; Traber J. et al. ., TIPS, 8,437,1987).

Receptor binding studies

^a i adrenergic 5-HT _1A serotonergic RECEPTOR / LIGAND Conditions [-Hlprazosin 1-H18-OH-DPAT [nM] ligand 0.35 1.0 preparation (c.m.p.) lml lml 10 mg / ml 10 mg / ml incubation buffer * Tris HCl Tris HCl 50 mM 50 mM pH7,4 pH7,4 nonspecific binding prazosin 5-HT 2μΜ 10 μΜ incubation 25 ° C 25 ° C 30 min 30 min

c.m.p. = impure membrane preparation;

* = contains ascorbic acid, 1%, and pargillin, 10 μΜ

153

The incubations were terminated after a reasonable time (see table) by rapid filtration through Whatman GF / B filters using a Brandel cell collector. The filters were washed 2 times with 15 ml of ice-cold buffer (see table). The radioactivity remaining on the filters was determined by liquid scintillation counting. Non-specific binding (which was generally 10 to 30%) was determined by the addition of high concentrations of specific attenuators (see table). All compounds were initially tested at a concentration of 1 x 10 ⁴ M and a complete competitive curve (up to a concentration of 10 ⁴¹ M) was determined in the presence of significant attenuation activity. All samples were used in perennial.

The competitive curves were always analyzed (to determine IC ₅₀ values) by nonlinear adjustment of the curve to the logistic equation by the method reported by De Lean et al. (Am. J., Physiol., 235, E97, 1978), using the ALLFIT program [available to the public at the National Institutes of Health (NIH) Bethesda, Maryland, USA] and written for an IBM computer PC.

Contractions of K * induced rat bladder bands

The whole rat bladder was removed and immediately placed in Krebs solution heated to 37 ° C. The detrusor strips (20 to 30 mm long, 1-2 mm wide) were cut from the vault of the bladder. Each strip was placed in a 10 ml organ bath and connected under a constant load of 1 g to an isometric elongation meter (DY-1 Basile, Comerio, Varese, Italy). Contractions were recorded with a Basile 7070 polygraph. After 60 minutes of equilibration time, the bands were released to a final concentration of 80 mM KC1. This resulted in a rapid phase contraction followed by a slowly following and lasting tonic component. Once the tonic contraction was stable, the bands were washed and a new contraction was induced 30 minutes later. After recording two or more reproducible responses, baths were added to one concentration of the test drugs and 30 minutes later caused a new contraction. The test groups consisted of at least two preparations taken from different animals for each concentration of the test drug. IC ₅₀ values of agonist-induced contraction inhibition were determined by linear regression analysis.

Effects on urethral contractions and blood pressure in dogs

The experiments were performed according to the method of Imagawe et al. (J. Pharmacol. Methods, 22,103-111, 1989) with these essential modifications: Adult male males of 8 to 10 kg weight were anesthetized with pentobarbital sodium (30 mg / kg iv and 2 mg / kg / h iv) ,

154 were intubated and spontaneously ventilated with air space. In order to control systemic blood pressure (BP), a polyethylene catheter was introduced into the aortic arch of the right common carotis artery.

The collateral part of the left femoral vein was fitted with an anesthetic infusion cannula and a cannula was administered into the right femoral vein to administer the drug. For intraarterial (ia) injection of norepinephrine (NA), a polyethylene catheter was introduced into the inferior abdominal aorta through the external ileus artery. Through this procedure, NA was selectively distributed to the lower urinary tract. A midline laparotomy revealed the urinary bladder and adjacent urethra. To prevent bladder filling, both urethra were fitted with cannulae and the urine was discharged to the outside. In order to record prostatic urethral pressure, a catheter with a micro-tip (6F) was introduced through the external urethra meatus and pulled back until the pressure transducer was placed in the prostatic urethra. A ligature was attached between the bladder neck and urethra to isolate the urethral response and prevent any interaction with the bladder. A second ligature was placed around the micro-tip catheter on the external urethral meatos to attach the catheter itself. After a stabilization period following surgery (30 min) in which arterial and prostatic urethral pressure were continuously monitored as basal values, NA was given at intervals of 10 minutes. The dose of NA that was chosen was such that caused at least a 100% increase in urethral pressure. The test compounds were administered iv in a cumulative manner at 15 to 20 min intervals between administrations. La. Norepinephrine injections were repeated approximately 5 minutes after each dosing of the test compound. Dose response curves were constructed by applying percentage inhibition of urethral pressure (NA-induced) rise and percentage decrease in blood pressure induced by the test compound. The ED ^ for diastolic blood pressure (dose causing 25% reduction) and ID ₅₀ (dose causing 50% inhibition of NA induced urethral pressure rise) were calculated by linear regression analysis.

Results

The compounds prepared in the examples were tested according to the above methods and the results are given below in the tables together with the comparative results for the reference standards used. Compounds having a receptor affinity (IC ₅₀ value) lower than about 500 nM are generally considered to have good affinity. Compounds with IC ₅₀ values less than 100 nM are generally preferred.

rat bladder

155

TABLE I

Binding to Acute Toxicity in Mice Stimulation Receptors

«, (nM) 5-HT _ta LDso i.p. (mg / kg) p.o. sK + ic ₅₀ (mM) Phase-tone contractions 550 55 346 1732 20 19 621 > 3000 107 1000 233 86 155 384 1915 66 111 > 500 1915 29 9 247 297 2.9 3.0 68 229 > 1000 > 3000 10,0 10,0 61 6 140 559 8 131 306 496 220 1050 345 778 1.6 2.2 59 910 299 608 8.8 3.8 270 > 1000 457 3000 165 340 > 1000 > 3000 169 85 297 594 2.7 2.5 17 33 297 566 117 48 > 500 > 2000 690 212 > 1000 > 3000 270 > 1000 > 500 > 2000 23 124 399 > 3000 1.0 0.8 120 96 203 1127 86 45 730 > 3000 10,0 10,0 119 46 301 > 2000 10,0 > 10 17 38 399 > 2000 10,0 10,0 30 34 > 500 2.8 3.6 15 8 329 959 18 54 > 500 > 2000 32 77 > 500 > 2000 20 344 > 500 > 2000 90 170 > 1000 > 3000

156

Table I (continued)

Compound Example no. Binds to receptie Acute toxicity in mice Stimulation LD50 i.p. (mg / kg) p.o. rat bladder sK + IC ₅₀ (/ iM) Contractions of phase tonic ic ₅₀ “l (nM) 5-HT ,, 40 75 83 140 349 0.5 0.9 41 43 53 399 2241 0.7 1.4 42 111 39 459 2163 10.0 10.0 43 166 > 1000 44 685 201 84 399 0.6 0.5 45 15 106 329 1727 46 86 23 47 36 23 330 1047 2.7 5.2 48 104 5 500 1914 49 152 9 432 > 2000 50 39 300 211 299 51 22 84 > 500 > 2000 52 89 2 127 224 53 7 41 127 1020 54 35 143 106 421 55 291 > 1000 128 > 2000 56 25 748 > 500 57 69 > 1000 500 > 2000 58 > 1000126 258 508 59 5 9 > 500 278 60 25 45 203 329 61 36 11 315 592 62 252 278 128 344 63 194 99 309 479 64 40 11 65 113 26 66 57 56 601 67 4 4 508 1868

157

Table 1 (continued

Compound Binding to receptors

Example no. ic ₅₀ «1 (nM) 5-HT _1a ld ₅₀ ip (mg / kg) p.o. 68 29 13 69 16 87 344 70 53 85 > 500 1868 71 108 69 72 145 111 479 > 2000 73 6 89 202 462 74 178 482 75 147 15 78 18 116 79 77 141 > 500 > 2000 80 28 162 81 13 81 83 30 5 84 5 2 85 16 14 86 48 20 87 119 107 237 > 500 88 216 11 93 47 38 94 39 66 98 103 12 99 44 5 102 56 18 104 9 15 107 37 16 110 26 15 Flavoxate >> 1000 >> 1000 385 808

Acute toxicity in mice Stimulation of rat bladder sK +

IC _5O 0xM) Contractions of phase tonic

158

Table II

Effects on urethral contractility and blood pressure in dogs

SDoiina Example no. Urethra ed ₅₀ (Ag / kg) DBP ED ^ (/ ig / kg) DBP / urethra relationship 5 37,0 1074 29.0 13 16.0 215 13,4 17 10,0 6.2 0.6 * 21 6.6 127 19,2 27 3.2 9.8 3.1 * 40 11,0 152 13,8 41 57,0 745 13,1 42 31.0 404 13,0 45 16.4 186 11.3 47 35,0 530 15.1 prazosin 3.6 6.6 1.8 * terflavoxate > 10000 6060 -

Urethra: active dose for 50% inhibition of norepinephrine-induced urethral contraction

DBP: the active dose for a 25% decrease in diastolic blood pressure

DBP / urethra: active dose ratio (selectivity index) * indiscriminate: significant effects on both urethra and DBP

Effective plural

The following are guidelines for effective oral, parenteral or intravenous dose ranges, expressed in mg / kg body weight per day for calf use:

(a) Obstructive disorders of the lower urinary tract generally 0.001 - 20

159

priority most priority ** 0.05 -1 0.3 (b) As antihypertensives: general 0.01 - 20 preferably 0,1-5 most preferred ** 1 ( ^c ) As anxiolytics - antidepressants: in general 0.01 - 20 preferably 0.05 - 5 most preferred ** 0.5 (d) As bladder spasmolytics: general 0.01 - 20 preferably 0,02-10 most preferred ** 2

** The most preferred values relate to oral dosing. Intravenous dosing should be 10 to 100 times lower.

Patients in need of treatment with the compounds and preparations of the invention also include people who have one or more symptoms of depression (as defined, e.g., in Harrison's Principles of Intemal Medicine, XII Ed., McGraw-Hill, Inc., pp. 2124) or people who show symptoms of anxiety (Harrison's, supra, pp. 2131-2134).

Doses for selective use, ie doses that are effective in the lower urinary tract with no significant effect on blood pressure, depend on the particular compound used, but generally up to 4 times ED _{50 of the} selective compound can be administered without significant effect on blood pressure. Only through routine experiments, further improvements and optimization of doses are possible.

The effective compounds of the invention may be administered orally, e.g. with an inert diluent or an edible carrier, or may be enclosed in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the effective compounds of the invention may be incorporated with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. These preparations should contain at least 0.5% of the active compound, but the amount of the active ingredient can be varied depending on the particular form and may be applied between 5 to about 70% by weight of the unit. The amount of active compound in such preparations is such that it will be suitably obtained

160 dose, although the desired dose can be achieved by administering several dosage forms. Preferred preparations and preparations of the invention are prepared so that the oral dosage unit contains between 1.0 and 300 milligrams of the active compound.

Tablets, pills, capsules, lozenges and the like. they may also contain the following ingredients: a binder such as microcrystalline cellulose, tragacanth or gelatin; excipient such as starch or lactose, disintegrating agent such as alginic acid, Primogel, corn starch, etc .; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silica and a sweetener such as sucrose or saccharin or a flavoring agent such as peppermint, methylsalicylate or orange flavor. If the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as fatty oil. Other dosage unit forms may contain other various materials that alter the physical form of the dosage unit, such as e.g. coverings. Thus, tablets or pills may be coated with sugar, Selak or other intestinal agents. The syrup may contain, in addition to the active compounds, as sucrose sweetener and certain preservatives, colorants, colors and flavors. The materials used in the preparation of such various preparations must be pharmaceutically pure and non-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into solution or suspension. These preparations should contain at least 0.1% of the active compound but may vary between 0.5 and about 30% by weight of the active compound. The amount of active compound in such preparations is such that a suitable dose is obtained. Preferred preparations and preparations of the invention are prepared so that the parenteral dosage unit contains between 0.2 to 100 mg of the active compound. Solutions or suspensions may also include the following ingredients: sterile diluent such as water for injections, saline, non-volatile oils, polyethylene glycols, glycerin, propylene glycol and other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamintetraacetic acid; buffers such as acetates, citrates or phosphates, and tonicity adjusting agents such as sodium chloride or dextrose. Bottles for parenteral multiple doses may be made of glass or plastic material.

Claims (9)

A compound of general formula I in which 2222 stands for single or double bond; X represents an oxygen or sulfur atom or an imino, alkylimino, sulfinyl or sulfonyl group; W represents a valence bond or a carbonyl, thiocarbonyl, methylene or hydroxymethylene group; R ₂ represents a hydrogen atom or an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl or aroyl group; wherein the substituents for the aforementioned substituted groups are one or more halogen atoms and / or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino or benzoyl groups; R ₃ represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy or aralkoxy group; R ₆ represents a hydrogen or halogen atom or a nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino, cyano, hydroxy, alkoxy or alkyl group; R ₇ represents a hydrogen atom or an alkoxy group; Y means one of the following groups, each of which is used such that its left end is an end that attaches to the heterobicyclic ring and its right end is an end that attaches to group Z 162 (Yl) -CO-, (Υ2) -COO-, (Υ3) -CONH-, (Υ4) -CON (CH ₃ ) -, (Υ5) -CON (OH) -, (Υ6) -CH (OH) -, (Υ7) -CH (Oalkyl) -, (Υ8) -CH = CH-, (Υ9) -CH = CH-COO-, (ΥΙΟ) -CH = CH-CONH-, (Υ11) -CH = NO-, (Υ12) -CH, -, (Υ13) -C ^ COO-, (Υ14) -CH ₂ CONH-, (Υ15) -ch ₂ nh-, (Υ16) -CH ₂ N (CH ₃ ) -, (Υ17) -CH ₂ N (COCH ₃ ) -, (Υ18) -CH ₂ N (CONH ₂ ) -, (Υ19) -ch ₂ nhco- (Υ20) -CH ₂ N (CH ₃ ) CO-, (Υ21) -ch ₂ nh-conh-, (Υ22) -CH ₂ NHSO ₂ -, (Υ23) -CH ^ O-, (Υ24) -CI ^ S-, (Υ25) -ch ₂ so-, (Υ26) -OE ^ SO, -, (Υ27) -CH ₂ SO ₂ NH-, (Υ28) -CH ₂ SO ₂ N (CH ₃ ) -, (Υ29) -NH-, (Υ3Ο) -N (CH ₃ ) -, (Υ31) -NtCOCHJ-, (Υ32) -NtCONHJ-, (Υ33) -NHCO-, (Υ34) -NtCHJCO-, (Υ35) -NH-CONH- 163 (Υ36) -nhso ₂ -, (Υ37) -O-, (Υ38) -S-, (Υ39) -SO-, (Υ40) -so ₂ -, (Υ41) -so ₂ nh-, (Υ42) -SO ₂ N (CH ₃ ) -, (Υ43) -CONHO-, (Υ44) -CON (COCH ₃ ) -, (Υ45) -CSNH-, (Υ46) -CSN (CH ₃ ) -, (Υ48) -NHCOO- in (Υ49) -COS-; Z represents a straight or branched alkylene group of 1 to 6 carbon atoms having optionally one hydroxy substituent; and B stands for one of the following groups: (BI) tl Vg / in which Q represents a methylene or ethylene group and A represents one of the following groups: (Al) a phenyl group substituted by one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups, (A2) 2-pyrimidinyl group and (A3) a group of the general formula 164 which - as defined above and E represents an oxygen atom or a valence bond, (B2) / L in which each represents 1 ^ and L ₂ are independently a hydrogen atom, a phenyl, 4-fluorobenzoilno or 2-oxo-l-benzimidazolyl group or a group of the general formula (CH ₂ ) _n -OA wherein n is 0,1 or 2 and A is defined as above, provided that both L ₂ do not represent both hydrogen atoms, (B3) in which each of R ₁₀ and R _n independently are a hydrogen atom or an alkoxy or alkylthio group, R ₁₂ represents a hydrogen atom or an alkyl group and n is 2 or 3, 165 (Β4) -N-CH in which R _{12 is} defined as above and R ₁₃ represents a hydrogen atom or an alkoxy group, and (B5) in which R _{12 is} defined as above, or a prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt thereof compounds. A compound according to claim 1, characterized in that - represents a double bond, X stands for oxygen atom, W represents a carbonyl group, R ₂ represents a phenyl group, R3 represents a methyl group, R ₆ represents a hydrogen atom and R 1 represents a hydrogen atom. Compound according to claim 1 or 2, characterized in that Y represents one of the groups Y ₂ , Y ₃ , Y ₃₇ , Υ ^ or Y _4r 166 Compound according to any one of the preceding claims, characterized in that Z represents a trimethylene or tetramethylene group. Compound according to any one of the preceding claims, characterized in that B represents one of the groups Β _χ or B ₃ . Compound according to any one of the preceding claims, characterized in that B represents a 4 (2-methoxyphenyl) -1-piperazinyl group. A compound according to any of the preceding claims, characterized in that Y, Z and B together represent a 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl group. A compound according to claim 1, characterized in that any of the following 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2phenyl-4H -1-benzopyran, 8- {2- [4- (2-methylphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {2- [4- (2-Ethoxyphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxopropyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl} -propoxycarbonyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-chlorophenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- [3- (4-Phenyl-1-piperazinyl) -propoxycarbonyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -2-methyl-2-propoxycarbonyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 167 8- {3- [2- (2-Methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H · 1- benzopyran, 8- [3- (4-Phenyl-1-piperazinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran, 8- {1-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {1-hydroxy-2- [4- (2-methylphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {1-hydroxy-2- [4- (2-ethoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {1-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {1-hydroxy-4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {1-ethoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {N-acetyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- [4- (2-Methoxyphenyl) -1-piperazinylacetamidomethyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] -acetamidomethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {2- [2- (2-Ethoxyphenoxy) -ethylamino] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, hydrochloride, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylthiomethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfinylmethyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfonylmethyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylamino} -3-methyl-4-oxo-2-phenyl-4H-1668 benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylamino} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propionamido} -3-methyl-4-oxo-2-phenyl-4H-1 benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylureido} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {5- [4- (2-Methoxyphenyl) -1-piperazinyl] -pentyloxy} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-oxo-1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {2- [2- (2,6-dimethoxyphenoxy) -ethylamino] -ethoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylthio} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-Carbamoyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran, 169 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxobutyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- (3- (2- (1,4-benzodioxanyl) methylamino] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- [3- (4-Phenyl-1-piperidinyl) -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- (3- (4,4-diphenyl-1-piperidinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (4-Fluorobenzoyl) -1-piperidinyl] -propyl-carbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-Oxo-1-benzimidazolinyl) -1-piperidinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- [3- [4- (2-pyrimidinyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-hydroxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylsulfamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [N-methyl-2- (2-methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propionamido} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-phenyl-4-oxo-4H-benzopyran, 8- (3 - ((3,4-dihydro-1-oxo-2H-naphthyl) -methylamino] -propylcarbamoyl} -3-methyl-4-oxo 2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonylmethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {N- (2-tetrahydropyranyloxy) -3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylramido} -3-methyl-4-oxo-2-phenyl170 4H-1-benzopyran, E-8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxyiminomethyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {N-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, E-8- <2- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -ethenyl> -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfinyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [3- (2-Methoxyphenoxy) -propylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [2- (2-methylthiophenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [2- (2,6-dimethoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, (E) -8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -1-butenyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, (E) -8- <2- {2- [4- (2- methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -ethenyl> -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylcarbamoylmethyl} -4-oxo-2-phenyl-4H-benzopyran, 8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) 4-piperazinyl] -ethylsulfonylamino} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylthiocarbamoyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-hydroxymethyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dihydro-4-oxo-4H-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-bromo-3-methyl-4-oxo171 2 "phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methoxy-3-methyl-4-oxo 2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3,6-dimethyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-6-nitro-4-oxo2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-amino-3-methyl-4-oxo2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-ethylamino-3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-dimethylamino-3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-benzoylphenyl) -3methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dimethyl-4-oxo-4H1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (t-butyl) -3-methyl4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-cyclohexyl-3-methyl4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (2-furyl) -3-methyl4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-thienyl4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-benzothiopyran, 172 (E) -8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (2-styryl) -4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-2- (4-methylphenyl) 4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-methoxyphenyl) -3methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-fluorophenyl) -3methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanesulfonylamino-3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-2- (4-nitrophenyl) 4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-diethoxyphosphonyloxy3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran, 8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-benzoyl-3-ethyl-benzo [bfuran; or a prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt of such compound. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt of such compound admixed with a pharmaceutically acceptable diluent or carrier. For Recordati S.A., Chemical and Pharmaceutical Company: PATENT PJSARNA ΓΑΝΑ 22621-III-93 / LZ 173 SUMMARY Heterobicyclic compounds Compounds of general formula are described R R • R Υ-Ζ-Β Heteroatom X is preferably oxygen, but may have other meanings. The W group is preferably a carbonyl group but may have other meanings. The preferred heterocyclic ring is thus a 4-oxo-4H-1-benzopyran ring. This may have different substituents R ₂ , R ₃ , R ₆ and R 4. Y is a linking group selected from a wide variety, but includes -COO-, -CONH-, -0-, -S0 ₂ -, and -S0 ₂ NH-. Z is an alkylene chain and B is a complex amine.These compounds and their prodrugs, enantiomers, diastereoisomers, N-oxides, and pharmaceutically acceptable salts are useful for the treatment of urinary tract hypertension and disorders related to benign prostatic hypertrophy and for the treatment of others diseases.